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Find video protocols related to scientific articles indexed in Pubmed.
Variants in Striatin Gene Are Associated With Salt-Sensitive Blood Pressure in Mice and Humans.
Hypertension
PUBLISHED: 11-05-2014
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Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor's rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.
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Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin.
Curr. Opin. Nephrol. Hypertens.
PUBLISHED: 07-30-2014
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Aldosterone's functions and mechanisms of action are different depending on the tissue and the environmental condition. The mineralocorticoid receptor is present in tissues beyond epithelial cells, including the heart and vessels. Furthermore, aldosterone has direct adverse effects by both genomic and rapid/nongenomic actions not only through a nuclear receptor but also through caveolae-mediated intracellular events. Also, multiple environmental-genetic interactions play an important role in salt-sensitive hypertension (SSH) and aldosterone modulation. These findings have reshaped our vision of aldosterone's role in cardiovascular pathophysiology. This review describes new mediators of aldosterone's mechanisms of action: lysine-specific demethylase 1 (LSD1), caveolin 1 (cav-1) and striatin.
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Estrogen receptor inhibits mineralocorticoid receptor transcriptional regulatory function.
Endocrinology
PUBLISHED: 07-22-2014
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The steroid hormone aldosterone (aldo) contributes to cardiovascular disease in animal models and in humans. Aldo activates the mineralocorticoid receptor (MR), a hormone-activated transcription factor, and indeed, pharmacological MR inhibition improves cardiovascular outcomes. Because the incidence of cardiovascular disease is lower in premenopausal women, we hypothesized that estrogen (E2) signaling through the estrogen receptor (ER) may protect the vasculature by inhibiting the detrimental effects of aldo signaling through the MR. We demonstrate that E2-activated ER inhibits MR-mediated gene transcription from the mouse mammary tumor virus reporter in human embryonic kidney-293 cells. In contrast, aldo-activated MR does not affect ER-mediated gene transcription. The ER? N terminus (amino acids 1-253) containing part of the DNA-binding domain is sufficient to inhibit MR genomic function, although point mutations reveal that DNA binding, ligand-independent activation, and rapid nongenomic ER? signaling are not required for this effect. Furthermore, ER? and MR are part of a complex in cell lysates, with amino acids 1-233 of the ER? N terminus being sufficient to complex with the MR. Overall, the ability of ER? to inhibit MR-mediated gene transcription correlates with the ability of ER? segments to both localize to the nucleus and complex with the MR. In cultured vascular endothelial cells expressing ER?, E2 inhibits aldo induction of the vascular MR target gene intercellular adhesion molecule-1 (ICAM-1). ICAM-1 induction by endothelial MR is known to promote vascular inflammation that could contribute to the mechanism of aldo-induced atherosclerosis. E2 also inhibits aldo induction of ICAM-1 protein and prevents aldo-enhanced leukocyte adhesion to endothelial cells. These studies support a new model in which E2-activated ER in endothelial cells forms a complex with MR in the nucleus to modulate MR regulation of the proinflammatory gene ICAM-1. Estrogen inhibition of MR regulation of genes that contribute to cardiovascular disease may be a new mechanism by which premenopausal women are protected from cardiovascular disease.
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Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk.
Hypertension
PUBLISHED: 03-24-2014
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Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (?=-4.60; P<0.0001) and higher SASSI (?=-58.63; P=0.001) predicted lower RPF and a blunted RPF response to sodium loading and angiotensin II infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (P<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (P<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.
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Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action.
Endocrinology
PUBLISHED: 03-21-2014
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The cellular responses to steroids are mediated by 2 general mechanisms: genomic and rapid/nongenomic effects. Identification of the mechanisms underlying aldosterone (ALDO)'s rapid vs their genomic actions is difficult to study, and these mechanisms are not clearly understood. Recent data suggest that striatin is a mediator of nongenomic effects of estrogen. We explored the hypothesis that striatin is an intermediary of the rapid/nongenomic effects of ALDO and that striatin serves as a novel link between the actions of the mineralocorticoid and estrogen receptors. In human and mouse endothelial cells, ALDO promoted an increase in phosphorylated extracellular signal-regulated protein kinases 1/2 (pERK) that peaked at 15 minutes. In addition, we found that striatin is a critical intermediary in this process, because reducing striatin levels with small interfering RNA (siRNA) technology prevented the rise in pERK levels. In contrast, reducing striatin did not significantly affect 2 well-characterized genomic responses to ALDO. Down-regulation of striatin with siRNA produced similar effects on estrogen's actions, reducing nongenomic, but not some genomic, actions. ALDO, but not estrogen, increased striatin levels. When endothelial cells were pretreated with ALDO, the rapid/nongenomic response to estrogen on phosphorylated endothelial nitric oxide synthase (peNOS) was enhanced and accelerated significantly. Importantly, pretreatment with estrogen did not enhance ALDO's nongenomic response on pERK. In conclusion, our results indicate that striatin is a novel mediator for both ALDO's and estrogen's rapid and nongenomic mechanisms of action on pERK and phosphorylated eNOS, respectively, thereby suggesting a unique level of interactions between the mineralocorticoid receptor and the estrogen receptor in the cardiovascular system.
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Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice.
J. Pharmacol. Exp. Ther.
PUBLISHED: 11-26-2013
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Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav-1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1(-/-) mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1(-/-) mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1(-/-) > WT and did not change with metformin. Phenylephrine (Phe)- and KCl-induced aortic contraction was in cav-1(-/-) < WT; endothelium removal, the nitric-oxide synthase (NOS) blocker l-NAME (N(?)-nitro-l-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1(-/-) > WT, abolished by endothelium removal, l-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1(-/-) than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1(-/-) > WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1(-/-). Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1(-/-) mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states.
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Human Interventions to Characterize Novel Relationships Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone.
Hypertension
PUBLISHED: 11-04-2013
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Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.
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Computer-controlled stimulation for functional magnetic resonance imaging studies of the neonatal olfactory system.
Acta Paediatr.
PUBLISHED: 03-07-2013
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Olfactory sensation is highly functional early in human neonatal life, with studies suggesting that odours can influence behaviour and infant-mother bonding. Due to its good spatial properties, blood oxygen level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) has the potential to rapidly advance our understanding of the neural activity which underlies the development of olfactory perception in this key period. We aimed to design an olfactometer specifically for use with neonatal subjects for fMRI studies of odour perception.
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Abnormal aldosterone physiology and cardiometabolic risk factors.
Hypertension
PUBLISHED: 02-11-2013
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Abnormal aldosterone physiology has been implicated in the pathogenesis of cardiometabolic diseases. Single aldosterone measurements capture only a limited range of aldosterone physiology. New methods of characterizing aldosterone physiology may provide a more comprehensive understanding of its relationship with cardiometabolic disease. We evaluated whether novel indices of aldosterone responses to dietary sodium modulation, the sodium-modulated aldosterone suppression-stimulation index (SASSI for serum and SAUSSI for urine), could predict cardiometabolic risk factors. We performed cross-sectional analyses on 539 subjects studied on liberal and restricted sodium diets with serum and urinary aldosterone measurements. SASSI and SAUSSI were calculated as the ratio of aldosterone on liberal (maximally suppressed aldosterone) to the aldosterone on restricted (stimulated aldosterone) diets and associated with risk factors using adjusted regression models. Cardiometabolic risk factors associated with either impaired suppression of aldosterone on liberal diet, or impaired stimulation on restricted diet, or both; in all of these individual cases, these risk factors associated with higher SASSI or SAUSSI. In the context of abnormalities that constitute the metabolic syndrome, there was a strong positive association between the number of metabolic syndrome components (0-4) and both SASSI and SAUSSI (P<0.0001) that was independent of known aldosterone secretagogues (angiotensin II, corticotropin, potassium). SASSI and SAUSSI exhibited a high sensitivity in detecting normal individuals with zero metabolic syndrome components (86% for SASSI and 83% for SAUSSI). Assessing the physiological range of aldosterone responses may provide greater insights into adrenal pathophysiology. Dysregulated aldosterone physiology may contribute to, or result from, early cardiometabolic abnormalities.
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Activation of the mineralocorticoid receptor increases striatin levels.
Am. J. Hypertens.
PUBLISHED: 11-17-2011
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Aldosterone (ALDO), a critical regulator of sodium homeostasis, mediates its effects via activation of the mineralocorticoid receptor (MR) through mechanisms that are not entirely clear. Striatin, a membrane associated protein, interacts with estrogen receptors in endothelial cells.
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Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 08-26-2011
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Histone methylation, a determinant of chromatin structure and gene transcription, was thought to be irreversible, but recent evidence suggests that lysine-specific demethylase-1 (LSD1, Kdm1a) induces demethylation of histone H3 lysine 4 (H3K4) or H3K9 and thereby alters gene transcription. We previously demonstrated a human LSD1 phenotype associated with salt-sensitive hypertension. To test the hypothesis that LSD1 plays a role in the regulation of blood pressure (BP) via vascular mechanisms and gene transcription, we measured BP and examined vascular function and endothelial nitric oxide (NO) synthase (eNOS) expression in thoracic aorta of male wild-type (WT) and heterozygous LSD1 knockout mice (LSD1(+/-)) fed either a liberal salt (HS; 4% NaCl) or restricted salt diet (LS; 0.08% NaCl). BP was higher in LSD1(+/-) than WT mice on the HS diet but not different between LSD1(+/-) and WT mice on the LS diet. Further examination of the mechanisms of this salt-sensitive hypertension in LSD1(+/-) mice on the HS diet demonstrated that plasma renin activity and plasma levels and urinary excretion of aldosterone were less in LSD1(+/-) than WT, suggesting suppressed renin-angiotensin-aldosterone system. In contrast, phenylephrine (Phe)-induced aortic contraction was greater in LSD1(+/-) than WT mice on the HS diet. Treatment of aortic rings with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a blocker of guanylate cyclase) enhanced Phe contraction in LSD1(+/-) compared with WT mice on the HS diet. Acetylcholine (Ach)-induced relaxation was less in LSD1(+/-) than WT mice on the HS diet. Endothelium removal or pretreatment with N(?)-nitro-L-arginine methyl ester (blocker of NOS) or ODQ abolished Ach-induced relaxation in aorta of WT but had minimal effect in LSD1(+/-). Vascular relaxation to sodium nitroprusside, an exogenous NO donor and guanylate cyclase activator, was decreased in LSD1(+/-) vs. WT mice on the HS diet. RT-PCR and Western blots revealed decreased eNOS mRNA expression and eNOS and guanylate cyclase protein in the heart and aorta of LSD1(+/-) compared with WT mice on HS diet. Thus, during the HS diet, LSD1 deficiency is associated with hypertension, enhanced vascular contraction, and reduced relaxation via NO-cGMP pathway. The data support a role for LSD1-mediated histone demethylation in the regulation of NOS/guanylate cyclase gene expression, vascular function, and BP during the HS diet.
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Replication and meta-analysis of the gene-environment interaction between body mass index and the interleukin-6 promoter polymorphism with higher insulin resistance.
Metab. Clin. Exp.
PUBLISHED: 08-19-2011
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Insulin resistance (IR) is a complex disorder caused by an interplay of both genetic and environmental factors. Recent studies identified a significant interaction between body mass index (BMI) and the rs1800795 polymorphism of the interleukin-6 gene that influences both IR and onset of type 2 diabetes mellitus, with obese individuals homozygous for the C allele demonstrating the highest level of IR and greatest risk for type 2 diabetes mellitus. Replication of a gene-environment interaction is important to confirm the validity of the initial finding and extend the generalizability of the results to other populations. Thus, the objective of this study was to replicate this gene-environment interaction on IR in a hypertensive population and perform a meta-analysis with prior published results. The replication analysis was performed using white individuals with hypertension from the Hypertensive Pathotype cohort (N = 311), genotyped for rs1800795. Phenotype studies were conducted after participants consumed 2 diets--high sodium (200 mmol/d) and low sodium (10 mmol/d)--for 7 days each. Measurements for plasma glucose, insulin, and interleukin-6 were obtained after 8 hours of fasting. Insulin resistance was characterized by the homeostatic model assessment (HOMA-IR). In Hypertensive Pathotype, BMI was a significant effect modifier of the relationship between rs1800795 and HOMA-IR; higher BMI was associated with higher HOMA-IR among homozygote CC individuals when compared with major allele G carriers (P = .003). Furthermore, the meta-analysis in 1028 individuals confirmed the result, demonstrating the same significant interaction between rs1800795 and BMI on HOMA-IR (P = 1.05 × 10(-6)). This rare replication of a gene-environment interaction extends the generalizability of the results to hypertension while highlighting this polymorphism as a marker of IR in obese individuals.
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Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart.
J. Endocrinol.
PUBLISHED: 07-11-2011
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Liberal or high-sodium (HS) intake, in conjunction with an activated renin-angiotensin-aldosterone system, increases cardiovascular (CV) damage. We tested the hypothesis that sodium intake regulates the type 1 angiotensin II receptor (AT(1)R), mineralocorticoid receptor (MR), and associated signaling pathways in heart tissue from healthy rodents. HS (1.6% Na(+)) and low-sodium (LS; 0.02% Na(+)) rat chow was fed to male healthy Wistar rats (n=7 animals per group). Protein levels were assessed by western blot and immunoprecipitation analysis. Fractionation studies showed that MR, AT(1)R, caveolin-3 (CAV-3), and CAV-1 were located in both cytoplasmic and membrane fractions. In healthy rats, consumption of an LS versus a HS diet led to decreased cardiac levels of AT(1)R and MR. Decreased sodium intake was also associated with decreased cardiac levels of CAV-1 and CAV-3, decreased immunoprecipitation of AT(1)R-CAV-3 and MR-CAV-3 complexes, but increased immunoprecipitation of AT(1)R/MR complexes. Furthermore, decreased sodium intake was associated with decreased cardiac extracellular signal-regulated kinase (ERK), phosphorylated ERK (pERK), and pERK/ERK ratio; increased cardiac striatin; decreased endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS), but increased peNOS/eNOS ratio; and decreased cardiac plasminogen activator inhibitor-1. Dietary sodium restriction has beneficial effects on the cardiac expression of factors associated with CV injury. These changes may play a role in the cardioprotective effects of dietary sodium restriction.
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Inflammation and hypertension: the interplay of interleukin-6, dietary sodium, and the renin-angiotensin system in humans.
Am. J. Hypertens.
PUBLISHED: 06-30-2011
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Prior evidence suggests a link between inflammation and hypertension. Interleukin-6 (IL-6) has been implicated in animal studies to play an important role in angiotensin II (ANGII)-mediated hypertension. The aim of this study was to examine the relationship of IL-6 and renin-angiotensin system (RAS) activity in human hypertension.
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Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome.
Hypertension
PUBLISHED: 06-20-2011
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We have found recently that exercise training is effective in the treatment of the postural orthostatic tachycardia syndrome (POTS). Whether this nondrug treatment is superior to "standard" drug therapies, such as ?-blockade, is unknown. We tested the hypothesis that exercise training but not ?-blockade treatment improves symptoms, hemodynamics, and renal-adrenal responses in POTS patients. Nineteen patients (18 women and 1 man) completed a double-blind drug trial (propranolol or placebo) for 4 weeks, followed by 3 months of exercise training. Fifteen age-matched healthy individuals (14 women and 1 man) served as controls. A 2-hour standing test was performed before and after drug treatment and training. Hemodynamics, catecholamines, plasma renin activity, and aldosterone were measured supine and during 2-hour standing. We found that both propranolol and training significantly lowered standing heart rate. Standing cardiac output was lowered after propranolol treatment (P=0.01) but was minimally changed after training. The aldosterone:renin ratio during 2-hour standing remained unchanged after propranolol treatment (4.1±1.7 [SD] before versus 3.9±2.0 after; P=0.46) but modestly increased after training (5.2±2.9 versus 6.5±3.0; P=0.05). Plasma catecholamines were not affected by propranolol or training. Patient quality of life, assessed using the 36-item Short-Form Health Survey, was improved after training (physical functioning score 33±10 before versus 50±9 after; social functioning score 37±9 versus 48±6; both P<0.01) but not after propranolol treatment (34±10 versus 36±11, P=0.63; 39±7 versus 39±5, P=0.73). These results suggest that, for patients with POTS, exercise training is superior to propranolol at restoring upright hemodynamics, normalizing renal-adrenal responsiveness, and improving quality of life.
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The association of plasma resistin with dietary sodium manipulation, the renin-angiotensin-aldosterone system, and 25-hydroxyvitamin D3 in human hypertension.
Clin. Endocrinol. (Oxf)
PUBLISHED: 06-10-2011
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Both resistin and vitamin D have been associated with the renin-angiotensin-aldosterone system (RAAS). We investigated the association between resistin and the RAAS, and resistin and vitamin D under controlled dietary sodium conditions.
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Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension.
J. Clin. Endocrinol. Metab.
PUBLISHED: 05-25-2011
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The co-occurrence of insulin resistance (IR) and hypertension is a heritable condition leading to cardiovascular complications. Caveolin-1 (CAV1), a gene previously associated with metabolic dysfunction in animal and cellular models, may be a marker for these conditions in humans.
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Mineralocorticoid receptor expression in human venous smooth muscle cells: a potential role for aldosterone signaling in vein graft arterialization.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 05-02-2011
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Experimental studies have suggested a role for the local renin-angiotensin-aldosterone system in the response to vascular injury. Clinical data support that aldosterone, via activation of the mineralocorticoid receptor (MR), is an important mediator of vascular damage in humans with cardiovascular disease. In mineralocorticoid-sensitive target tissue, aldosterone specificity for MR is conferred enzymatically by the cortisol-inactivating enzyme 11?-hydroxysteroid-dehydrogenase-2 (11?HSD2). However, the role of MR/aldosterone signaling in the venous system has not been explored. We hypothesized that MR expression and signaling in venous smooth muscle cells contributes to the arterialization of venous conduits and the injury response in vein bypass grafts. MR immunostaining was observed in all samples of excised human peripheral vein graft lesions and in explanted experimental rabbit carotid interposition vein grafts, with minimal staining in control greater saphenous vein. We also found upregulated transcriptional expression of both MR and 11?HSD2 in human vein graft and rabbit vein graft, whereas control greater saphenous vein expressed minimal MR and no detectable 11?HSD2. The expression of MR and 11?HSD2 was confirmed in cultured human saphenous venous smooth muscle cells (hSVSMCs). Using an adenovirus containing a MR response element-driven reporter gene, we demonstrate that MR in hSVSMCs is capable of mediating aldosterone-induced gene activation. The functional significance for MR signaling in hSVSMCs is supported by the aldosterone-induced increase of angiotensin II type-1 receptor gene expression that was inhibited by the MR antagonist spironolactone. The upregulation of MR and 11?HSD2 suggests that aldosterone-mediated tissue injury plays a role in vein graft arterialization.
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The Fok1 vitamin D receptor gene polymorphism is associated with plasma renin activity in Caucasians.
Clin. Endocrinol. (Oxf)
PUBLISHED: 04-28-2011
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25-Hydroxyvitamin D (25(OH)D) deficiency and excess activity of the renin-angiotensin system (RAS) are both associated with cardiovascular disease. Vitamin D interacts with the vitamin D receptor (VDR) to negatively regulate renin expression in mice; however, human studies linking genetic variation in the VDR with renin are lacking. We evaluated (i) whether genetic variation in the VDR at the Fok1 polymorphism was associated with plasma renin activity (PRA) in a population of hypertensives and a separate population of normotensives and (ii) whether the association between Fok1 genotype and PRA was independent of 25(OH)D levels.
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Renin gene polymorphism: its relationship to hypertension, renin levels and vascular responses.
J Renin Angiotensin Aldosterone Syst
PUBLISHED: 04-13-2011
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The renin gene has been previously reported to be associated with essential hypertension in a variety of ethnic groups. However, no studies have systematically evaluated the relationship between single nucleotide polymorphisms (SNPs) representing coverage of the entire renin gene and hypertension risk. To evaluate the association between renin gene variation and hypertension we investigated data on HyperPATH cohort with 570 hypertensive and 222 normotensive Caucasian subjects. Six tagging SNPs and resultant haplotypes were tested for associations with hypertension risk, followed by mean arterial pressure (MAP), plasma renin activity (PRA) and the change in MAP in response to angiotensin II (AngII) infusion (AngII ?MAP). The A allele of SNP rs6693954 and the haplotype containing rs6696954A were significantly associated with higher risk for hypertension (OR = 1.98, p = 0.0001; OR = 1.63 p = 0.0005, respectively). The same haplotype block was also associated with altered PRA levels and blunted AngII ?MAP (global p-value = 0.02, 0.047, respectively). Our results confirm that polymorphisms in the renin gene are associated with increased risk for hypertension in an independent cohort, and that the underlying mechanism may reside in the interaction of renin activity and vascular responsiveness to angiotensin II.
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Cell membrane-associated mineralocorticoid receptors? New evidence.
Hypertension
PUBLISHED: 04-11-2011
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The purpose of the present article is to provide an overview of plasma membrane steroid hormone receptors and their implications in nongenomic signaling. We especially focus on recent evidence supporting the notion of a possible membrane-associated aldosterone receptor, whether this receptor is different from the classic nuclear receptor, and the possible implications of such a receptor for nongenomic and genomic aldosterone effects in physiological and pathophysiological processes.
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A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism.
J. Hypertens.
PUBLISHED: 04-01-2011
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Eplerenone is claimed to be a more selective blocker of the mineralocorticoid receptor than spironolactone being associated with fewer antiandrogenic side-effects. We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism.
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The influence of body mass index and renin-angiotensin-aldosterone system activity on the relationship between 25-hydroxyvitamin D and adiponectin in Caucasian men.
Eur. J. Endocrinol.
PUBLISHED: 03-14-2011
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Previous studies have suggested that circulating adiponectin concentrations are associated positively with vitamin D and negatively with body mass index (BMI) but have not accounted for the influence of the renin-angiotensin-aldosterone system (RAAS) in this relationship. This is particularly relevant because increased RAAS activity is associated with obesity and is known to lower adiponectin levels. We evaluated the association between adiponectin and 25-hydroxyvitamin D (25(OH)D) after controlling RAAS activity with dietary sodium equilibration and also evaluated whether this relationship was influenced by BMI.
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The association of the angiotensinogen gene with insulin sensitivity in humans: a tagging single nucleotide polymorphism and haplotype approach.
Metab. Clin. Exp.
PUBLISHED: 02-08-2011
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The purpose of this study was to clarify the association of the angiotensinogen gene (AGT) with insulin sensitivity using single nucleotide polymorphism (SNP) and haplotype analyses in a white cohort. A candidate gene association study was conducted in white persons with and without hypertension (N = 449). Seventeen SNPs of the AGT gene and their haplotypes were analyzed for an association with homeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression model accounting for age, sex, body mass index, hypertension status, study site, and sibling relatedness was used to test the hypothesis. Nine of the 17 SNPs were significantly associated with lower HOMA-IR levels. Homozygous minor allele carriers of the most significant SNP, rs2493134 (GG), a surrogate for the gain-of-function mutation rs699 (AGT p.M268T), had significantly lower HOMA-IR levels (P = .0001) than heterozygous or homozygous major allele carriers (AG, AA). Direct genotyping of rs699 in a subset of the population showed similar results, with minor allele carriers exhibiting significantly decreased HOMA-IR levels (P = .003). Haplotype analysis demonstrated that haplotypes rs2493137A|rs5050A|rs3789678G|rs2493134A and rs2004776G|rs11122576A|rs699T|rs6687360G were also significantly associated with HOMA-IR (P = .0009, P = .02), and these results were driven by rs2493134 and rs699. This study confirms an association between the AGT gene and insulin sensitivity in white humans. Haplotype analysis extends this finding and implicates SNPs rs2493134 and rs699 as the most influential. Thus, AGT gene variants, previously shown to be associated with AGT levels, are also associated with insulin sensitivity; suggesting a relationship between the AGT gene, AGT levels, and insulin sensitivity in humans.
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Bleeding from peristomal varices: a complication of portal hypertension.
BMJ Case Rep
PUBLISHED: 01-01-2011
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Peristomal varices are a recognised complication of stomas in the presence of portal hypertension. There has been a progression of treatment options described in the literature, including the transjugular intrahepatic portosystemic shunt (TIPS). The use of TIPS, a percutaneous procedure allowing connection between the portal and systemic circulations within the liver, is a well-recognised method of treating the complications of portal hypertension. This report presents a case of peristomal varices successfully treated with TIPS and subsequently reviews the literature relating to its management.
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Short-axis 2D strain from speckle tracking predicts echocardiographic response to cardiac resynchronization therapy.
Echocardiography
PUBLISHED: 12-22-2010
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Two-dimensional (2D) strain imaging from speckle tracking is a Doppler independent technique allowing assessment of left ventricular (LV) strain (?); systolic strain rate (SRs) and early diastolic strain rate (SRe) in the radial and circumferential planes. We set out to investigate whether (i) these parameters facilitated assessment of dyssynchronous contraction and (ii) these measures could predict response to cardiac resynchronization therapy (CRT). MeTHODS AND RESULTS: Forty-one patients with severe, symptomatic heart failure on optimal medical therapy were recruited. Thirty-two healthy subjects were used as controls. Time to peak ?, SRs, and SRe of 6 LV segments were measured in the parasternal short axis prior to and 6 weeks post CRT implantation. Time delays between segments were then calculated and ANOVA assessed for prediction of response, classified as reduction in LV end systolic volume of >15%. 2D strain demonstrated significantly more dyssynchronous contraction in the heart failure population at baseline compared to healthy controls. Significant reduction in dyssynchrony was seen in ? and SRs following CRT, largely confined to those with evidence of remodeling. The time delay between peak circumferential SRs of opposing walls was the best predictor of reverse remodeling.
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Modulation of the BP response to diet by genes in the renin-angiotensin system and the adrenergic nervous system.
Am. J. Hypertens.
PUBLISHED: 11-18-2010
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Essential hypertension results from the interaction of several genetic and environmental factors. Identification of genetic factors that modulate blood pressure (BP) response to interventions can lead to improved strategies for prevention and control. The purpose of this study was to identify genes that modulate BP response to dietary interventions.
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Common variants at 10 genomic loci influence hemoglobin A?(C) levels via glycemic and nonglycemic pathways.
Nicole Soranzo, Serena Sanna, Eleanor Wheeler, Christian Gieger, Dörte Radke, Josée Dupuis, Nabila Bouatia-Naji, Claudia Langenberg, Inga Prokopenko, Elliot Stolerman, Manjinder S Sandhu, Matthew M Heeney, Joseph M Devaney, Muredach P Reilly, Sally L Ricketts, Alexandre F R Stewart, Benjamin F Voight, Christina Willenborg, Benjamin Wright, David Altshuler, Dan Arking, Beverley Balkau, Daniel Barnes, Eric Boerwinkle, Bernhard Böhm, Amélie Bonnefond, Lori L Bonnycastle, Dorret I Boomsma, Stefan R Bornstein, Yvonne Böttcher, Suzannah Bumpstead, Mary Susan Burnett-Miller, Harry Campbell, Antonio Cao, John Chambers, Robert Clark, Francis S Collins, Josef Coresh, Eco J C de Geus, Mariano Dei, Panos Deloukas, Angela Döring, Josephine M Egan, Roberto Elosua, Luigi Ferrucci, Nita Forouhi, Caroline S Fox, Christopher Franklin, Maria Grazia Franzosi, Sophie Gallina, Anuj Goel, Jurgen Graessler, Harald Grallert, Andreas Greinacher, David Hadley, Alistair Hall, Anders Hamsten, Caroline Hayward, Simon Heath, Christian Herder, Georg Homuth, Jouke-Jan Hottenga, Rachel Hunter-Merrill, Thomas Illig, Anne U Jackson, Antti Jula, Marcus Kleber, Christopher W Knouff, Augustine Kong, Jaspal Kooner, Anna Köttgen, Peter Kovacs, Knut Krohn, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Mark Lathrop, Cécile Lecoeur, Man Li, Mingyao Li, Ruth J F Loos, Jian'an Luan, Valeriya Lyssenko, Reedik Mägi, Patrik K E Magnusson, Anders Malarstig, Massimo Mangino, María Teresa Martínez-Larrad, Winfried März, Wendy L McArdle, Ruth McPherson, Christa Meisinger, Thomas Meitinger, Olle Melander, Karen L Mohlke, Vincent E Mooser, Mario A Morken, Narisu Narisu, David M Nathan, Matthias Nauck, Chris O'Donnell, Konrad Oexle, Nazario Olla, James S Pankow, Felicity Payne, John F Peden, Nancy L Pedersen, Leena Peltonen, Markus Perola, Ozren Polašek, Eleonora Porcu, Daniel J Rader, Wolfgang Rathmann, Samuli Ripatti, Ghislain Rocheleau, Michael Roden, Igor Rudan, Veikko Salomaa, Richa Saxena, David Schlessinger, Heribert Schunkert, Peter Schwarz, Udo Seedorf, Elizabeth Selvin, Manuel Serrano-Ríos, Peter Shrader, Angela Silveira, David Siscovick, Kjioung Song, Timothy D Spector, Kari Stefansson, Valgerdur Steinthorsdottir, David P Strachan, Rona Strawbridge, Michael Stumvoll, Ida Surakka, Amy J Swift, Toshiko Tanaka, Alexander Teumer, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Anke Tönjes, Gianluca Usala, Veronique Vitart, Henry Völzke, Henri Wallaschofski, Dawn M Waterworth, Hugh Watkins, H-Erich Wichmann, Sarah H Wild, Gonneke Willemsen, Gordon H Williams, James F Wilson, Juliane Winkelmann, Alan F Wright, , Carina Zabena, Jing Hua Zhao, Stephen E Epstein, Jeanette Erdmann, Hakon H Hakonarson, Sekar Kathiresan, Kay-Tee Khaw, Robert Roberts, Nilesh J Samani, Mark D Fleming, Robert Sladek, Goncalo Abecasis, Michael Boehnke, Philippe Froguel, Leif Groop, Mark I McCarthy, W H Linda Kao, Jose C Florez, Manuela Uda, Nicholas J Wareham, Inês Barroso, James B Meigs.
Diabetes
PUBLISHED: 09-21-2010
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Glycated hemoglobin (HbA?(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA?(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA?(c) levels.
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Low-salt diet increases insulin resistance in healthy subjects.
Metab. Clin. Exp.
PUBLISHED: 07-23-2010
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Low-salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects. Healthy individuals were studied after 7 days of LS diet (urine sodium <20 mmol/d) and 7 days of high-salt (HS) diet (urine sodium >150 mmol/d) in a random order. Insulin resistance was measured after each diet and compared statistically, unadjusted and adjusted for important covariates. One hundred fifty-two healthy men and women, aged 39.1 ± 12.5 years (range, 18-65) and with body mass index of 25.3 ± 4.0 kg/m(2), were included in this study. Mean (SD) homeostasis model assessment index was significantly higher on LS compared with HS diet (2.8 ± 1.6 vs 2.4 ± 1.7, P < .01). Serum aldosterone (21.0 ± 14.3 vs 3.4 ± 1.5 ng/dL, P < .001), 24-hour urine aldosterone (63.0 ± 34.0 vs 9.5 ± 6.5 ?g/d, P < .001), and 24-hour urine norepinephrine excretion (78.0 ± 36.7 vs 67.9 ± 39.8 ?g/d, P < .05) were higher on LS diet compared with HS diet. Low-salt diet was significantly associated with higher homeostasis model assessment index independent of age, sex, blood pressure, body mass index, serum sodium and potassium, serum angiotensin II, plasma renin activity, serum and urine aldosterone, and urine epinephrine and norepinephrine. Low-salt diet is associated with an increase in IR. The impact of our findings on the pathogenesis of diabetes and cardiovascular disease needs further investigation.
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The relationship between peroxisome proliferator-activated receptor-gamma and renin: a human genetics study.
J. Clin. Endocrinol. Metab.
PUBLISHED: 07-14-2010
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Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists often cause volume retention and edema. A relationship between PPARgamma and renin may play a role in this process.
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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.
Themistocles L Assimes, Hilma Holm, Sekar Kathiresan, Muredach P Reilly, Gudmar Thorleifsson, Benjamin F Voight, Jeanette Erdmann, Christina Willenborg, Dhananjay Vaidya, Changchun Xie, Chris C Patterson, Thomas M Morgan, Mary Susan Burnett, Mingyao Li, Mark A Hlatky, Joshua W Knowles, John R Thompson, Devin Absher, Carlos Iribarren, Alan Go, Stephen P Fortmann, Stephen Sidney, Neil Risch, Hua Tang, Richard M Myers, Klaus Berger, Monika Stoll, Svati H Shah, Gudmundur Thorgeirsson, Karl Andersen, Aki S Havulinna, J Enrique Herrera, Nauder Faraday, Yoonhee Kim, Brian G Kral, Rasika A Mathias, Ingo Ruczinski, Bhoom Suktitipat, Alexander F Wilson, Lisa R Yanek, Lewis C Becker, Patrick Linsel-Nitschke, Wolfgang Lieb, Inke R König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Wibke Reinhard, Janina Winogradow, Martina Grassl, Anika Grosshennig, Michael Preuss, Stefan Schreiber, H-Erich Wichmann, Christa Meisinger, Jean Yee, Yechiel Friedlander, Ron Do, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Liming Qu, Robert L Wilensky, William H Matthai, Atif N Qasim, Hakon Hakonarson, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent E Mooser, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, Nicola Martinelli, Oliviero Olivieri, Elisabetta Trabetti, Giovanni Malerba, Pier Franco Pignatti, Candace Guiducci, Daniel Mirel, Melissa Parkin, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Kiran Musunuru, Mark J Daly, Shaun Purcell, Sandra Eifert, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, , Willem H Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, Andreas Huge, Thomas Scheffold, Veikko Salomaa, Domenico Girelli, Christopher B Granger, Leena Peltonen, Pascal P McKeown, David Altshuler, Olle Melander, Joseph M Devaney, Stephen E Epstein, Daniel J Rader, Roberto Elosua, James C Engert, Sonia S Anand, Alistair S Hall, Andreas Ziegler, Christopher J O'Donnell, John A Spertus, David Siscovick, Stephen M Schwartz, Diane Becker, Unnur Thorsteinsdottir, Kari Stefansson, Heribert Schunkert, Nilesh J Samani, Thomas Quertermous.
J. Am. Coll. Cardiol.
PUBLISHED: 06-14-2010
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We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
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Menstrual cycle affects renal-adrenal and hemodynamic responses during prolonged standing in the postural orthostatic tachycardia syndrome.
Hypertension
PUBLISHED: 05-17-2010
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Approximately 500,000 American premenopausal women have the postural orthostatic tachycardia syndrome (POTS). We tested the hypothesis that in POTS women during orthostasis, activation of the renin-angiotensin-aldosterone system is greater, leading to better compensated hemodynamics in the midluteal phase (MLP) than in the early follicular phase of the menstrual cycle. Ten POTS women and 11 healthy women (controls) consumed a constant diet 3 days before testing. Hemodynamics and renal-adrenal hormones were measured while supine and during 2-hour standing. We found that blood pressure was similar, heart rate and total peripheral resistance were greater, and cardiac output and stroke volume were lower in POTS subjects than in controls during 2-hour standing. In controls, hemodynamic parameters were indistinguishable between menstrual phases. In POTS subjects, cardiac output and stroke volume were lower and total peripheral resistance was greater in the early follicular phase than MLP after 30 minutes of standing; however, blood pressure and heart rate were similar between phases. Plasma renin activity (9+/-6 [SD] versus 13+/-9 ng/mL per hour; P=0.04) and aldosterone (43+/-22 versus 55+/-25 ng/dL; P=0.02) were lower in the early follicular phase than MLP in POTS subjects after 2 hours of standing. Catecholamine responses were similar between phases. The percentage rate of subjects having presyncope was greater in the early follicular phase than MLP for both groups (chi(2) P<0.01). These results suggest that the menstrual cycle modulates the renin-angiotensin-aldosterone system and affects hemodynamics during orthostasis in POTS. The high estrogen and progesterone in the MLP are associated with greater increases in renal-adrenal hormones and presumably more volume retention, which improve late-standing tolerance in these patients.
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Sensitivity of NOS-dependent vascular relaxation pathway to mineralocorticoid receptor blockade in caveolin-1-deficient mice.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 04-02-2010
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Endothelial caveolin-1 (cav-1) is an anchoring protein in plasma membrane caveolae where it binds endothelial nitric oxide synthase (eNOS) and limits its activation, particularly in animals fed a high salt (HS) diet. Cav-1 also interacts with steroid receptors such as the mineralocorticoid receptor (MR). To test the hypothesis that vascular reactivity is influenced by an interplay between MR and cav-1 during HS diet, we examined the effects of MR blockade on NOS-mediated vascular relaxation in normal and cav-1-deficient mice. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) were fed for 14 days a HS (4% NaCl) diet with and without the MR antagonist eplerenone (Epl; 100 mg x kg(-1) x day(-1)). After systolic blood pressure (BP) was measured, the thoracic aorta was isolated for measurement of vascular reactivity, and the aorta and heart were used for measurement of eNOS and MR expression. BP was not different between WT + Epl and WT, but was higher in cav-1(-/-) + Epl than in cav-1(-/-) mice. Phenylephrine (Phe)-induced vascular contraction was less in cav-1(-/-) than WT, and significantly enhanced in cav-1(-/-) + Epl than in cav-1(-/-), but not in WT + Epl compared with WT. Endothelium removal and NOS blockade by N(omega)-nitro-l-arginine methyl ester (l-NAME) enhanced Phe contraction in cav-1(-/-), but not cav-1(-/-) + Epl. ACh-induced aortic relaxation was reduced in cav-1(-/-) + Epl versus cav-1(-/-), but not in WT + Epl compared with WT. Endothelium removal, l-NAME, and the guanylate cyclase inhibitor ODQ abolished the large ACh-induced relaxation in cav-1(-/-) and the remaining relaxation in the cav-1(-/-) + Epl but had similar inhibitory effect in WT and WT + Epl. Real-time RT-PCR indicated decreased eNOS mRNA expression in the aorta and heart, and Western blots revealed decreased total eNOS in the heart of cav-1(-/-) + Epl compared with cav-1(-/-). Vascular and cardiac MR expression was less in cav-1(-/-) than WT, but not in cav-1(-/-) + Epl compared with cav-1(-/-). Plasma aldosterone (Aldo) was not different between WT and cav-1(-/-) mice nontreated or treated with Epl. Thus in cav-1 deficiency states and HS diet MR blockade is associated with increased BP, enhanced vasoconstriction, and decreased NOS-mediated vascular relaxation and eNOS expression. The data suggest that, in the absence of cav-1, MR activation plays a beneficial role in regulating eNOS expression/activity and, consequently, the vascular function during HS diet.
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A mechanism for salt-sensitive hypertension: abnormal dietary sodium-mediated vascular response to angiotensin-II.
J. Hypertens.
PUBLISHED: 03-11-2010
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Several mechanisms have been proposed for salt-sensitive hypertension, with most focusing on impaired renal sodium handling. We tested the hypothesis that abnormalities in peripheral vascular responsiveness to angiotensin-II (ANGII) might also exist in salt-sensitive hypertension because of the interplay of the renin-angiotensin system and dietary sodium.
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Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.
Diabetes
PUBLISHED: 02-25-2010
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OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
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Aldosterone production and insulin resistance in healthy adults.
J. Clin. Endocrinol. Metab.
PUBLISHED: 02-03-2010
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Aldosterone production is associated with insulin resistance in obese and hypertensive subjects. However, its effect on insulin sensitivity in healthy subjects is not clear.
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Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II.
Endocrinology
PUBLISHED: 01-22-2010
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Caveolae are the major cellular membrane structure through which extracellular mediators transmit information to intracellular signaling pathways. In vascular tissue (but not ventricular myocardium), caveolin-1 (cav-1) is the main component of caveolae; cav-1 modulates enzymes and receptors, such as the endothelial nitric oxide synthase and the angiotensin II (AngII) type 1 receptor. Evidence suggests that AngII and aldosterone (ALDO) are important mediators of ventricular injury. We have described a model of biventricular damage in rodents that relies on treatment with N-omega-nitro-l-arginine methyl ester (L-NAME (nitric oxide synthase inhibitor)) and AngII. This damage initiated at the vascular level and was observed only in the presence of ALDO and an activated mineralocorticoid receptor (MR). We hypothesize that cav-1 modulates the adverse cardiac effects mediated by ALDO in this animal model. To test this hypothesis, we assessed the ventricular damage and measures of inflammation, in wild-type (WT) and cav-1 knockout (KO) mice randomized to either placebo or L-NAME/AngII treatment. Despite displaying cardiac hypertrophy at baseline and higher blood pressure responses to L-NAME/AngII, cav-1 KO mice displayed, as compared with WT, decreased treatment-induced biventricular damage as well as decreased transcript levels of the proinflammatory marker plasminogen activator inhibitor-1. Additionally, L-NAME/AngII induced an increase in cardiac MR levels in WT but not cav-1-ablated mice. Moreover and despite similar circulating ALDO levels in both genotypes, the myocardial damage (as determined histologically and by plasminogen activator inhibitor-1 mRNA levels) was less sensitive to ALDO levels in cav-1 KO vs. WT mice, consistent with decreased MR signaling in the cav-1 KO. Thus, we conclude that the L-NAME/AngII-induced biventricular damage is mediated by a mechanism partially dependent on cav-1 and signaling via MR/ALDO.
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New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U Jackson, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Anna L Gloyn, Cecilia M Lindgren, Reedik Mägi, Andrew P Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter Henneman, Harald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R B Perry, Josephine M Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F Voight, Heather M Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Felicity Payne, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Kristin Ardlie, Yavuz Ariyurek, Beverley Balkau, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Rafn Benediktsson, Amanda J Bennett, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Guillaume Charpentier, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Marilyn Cornelis, Gabe Crawford, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Christian Dina, Michael R Erdos, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Caroline S Fox, Rune Frants, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Christopher J Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, Samy Hadjadj, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Neelam Hassanali, Caroline Hayward, Simon C Heath, Serge Hercberg, Christian Herder, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Albert Hofman, Jennie Hui, Joe Hung, Bo Isomaa, Paul R V Johnson, Torben Jørgensen, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Valeriya Lyssenko, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Laura J McCulloch, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Mario A Morken, Sutapa Mukherjee, Silvia Naitza, Narisu Narisu, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Colin N A Palmer, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Wolfgang Rathmann, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Michael Roden, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Laura J Scott, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurethsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Barbara Thorand, Jean Tichet, Anke Tönjes, Tiinamaija Tuomi, André G Uitterlinden, Ko Willems van Dijk, Mandy van Hoek, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, G Bragi Walters, Kim L Ward, Hugh Watkins, Michael N Weedon, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Eleftheria Zeggini, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, , Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Andrew T Hattersley, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Andrew D Morris, Lars Lind, Lyle J Palmer, Frank B Hu, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, James S Pankow, Michael J Sampson, Johanna Kuusisto, Markku Laakso, Torben Hansen, Oluf Pedersen, Peter Paul Pramstaller, H Erich Wichmann, Thomas Illig, Igor Rudan, Alan F Wright, Michael Stumvoll, Harry Campbell, James F Wilson, Richard N Bergman, Thomas A Buchanan, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Timo T Valle, David Altshuler, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Timothy M Frayling, Luigi Ferrucci, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Cornelia M van Duijn, Yurii S Aulchenko, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Gonçalo R Abecasis, Nicholas J Wareham, Robert Sladek, Philippe Froguel, Richard M Watanabe, James B Meigs, Leif Groop, Michael Boehnke, Mark I McCarthy, Jose C Florez, Inês Barroso.
Nat. Genet.
PUBLISHED: 01-17-2010
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Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.
Richa Saxena, Marie-France Hivert, Claudia Langenberg, Toshiko Tanaka, James S Pankow, Peter Vollenweider, Valeriya Lyssenko, Nabila Bouatia-Naji, Josée Dupuis, Anne U Jackson, W H Linda Kao, Man Li, Nicole L Glazer, Alisa K Manning, Jian'an Luan, Heather M Stringham, Inga Prokopenko, Toby Johnson, Niels Grarup, Trine W Boesgaard, Cécile Lecoeur, Peter Shrader, Jeffrey O'Connell, Erik Ingelsson, David J Couper, Kenneth Rice, Kijoung Song, Camilla H Andreasen, Christian Dina, Anna Köttgen, Olivier Le Bacquer, François Pattou, Jalal Taneera, Valgerdur Steinthorsdottir, Denis Rybin, Kristin Ardlie, Michael Sampson, Lu Qi, Mandy van Hoek, Michael N Weedon, Yurii S Aulchenko, Benjamin F Voight, Harald Grallert, Beverley Balkau, Richard N Bergman, Suzette J Bielinski, Amélie Bonnefond, Lori L Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Thomas A Buchanan, Suzannah J Bumpstead, Christine Cavalcanti-Proença, Guillaume Charpentier, Yii-Der Ida Chen, Peter S Chines, Francis S Collins, Marilyn Cornelis, Gabriel J Crawford, Jérôme Delplanque, Alex Doney, Josephine M Egan, Michael R Erdos, Mathieu Firmann, Nita G Forouhi, Caroline S Fox, Mark O Goodarzi, Jurgen Graessler, Aroon Hingorani, Bo Isomaa, Torben Jørgensen, Mika Kivimäki, Peter Kovacs, Knut Krohn, Meena Kumari, Torsten Lauritzen, Claire Levy-Marchal, Vladimir Mayor, Jarred B McAteer, David Meyre, Braxton D Mitchell, Karen L Mohlke, Mario A Morken, Narisu Narisu, Colin N A Palmer, Ruth Pakyz, Laura Pascoe, Felicity Payne, Daniel Pearson, Wolfgang Rathmann, Annelli Sandbaek, Avan Aihie Sayer, Laura J Scott, Stephen J Sharp, Eric Sijbrands, Andrew Singleton, David S Siscovick, Nicholas L Smith, Thomas Sparsø, Amy J Swift, Holly Syddall, Gudmar Thorleifsson, Anke Tönjes, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T Valle, Gérard Waeber, Andrew Walley, Dawn M Waterworth, Eleftheria Zeggini, Jing Hua Zhao, , Thomas Illig, H Erich Wichmann, James F Wilson, Cornelia van Duijn, Frank B Hu, Andrew D Morris, Timothy M Frayling, Andrew T Hattersley, Unnur Thorsteinsdottir, Kari Stefansson, Peter Nilsson, Ann-Christine Syvänen, Alan R Shuldiner, Mark Walker, Stefan R Bornstein, Peter Schwarz, Gordon H Williams, David M Nathan, Johanna Kuusisto, Markku Laakso, Cyrus Cooper, Michael Marmot, Luigi Ferrucci, Vincent Mooser, Michael Stumvoll, Ruth J F Loos, David Altshuler, Bruce M Psaty, Jerome I Rotter, Eric Boerwinkle, Torben Hansen, Oluf Pedersen, Jose C Florez, Mark I McCarthy, Michael Boehnke, Inês Barroso, Robert Sladek, Philippe Froguel, James B Meigs, Leif Groop, Nicholas J Wareham, Richard M Watanabe.
Nat. Genet.
PUBLISHED: 01-17-2010
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Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
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Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats.
J. Endocrinol.
PUBLISHED: 07-31-2009
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We tested the hypothesis that 17beta-estradiol (E(2)) has dual effects on the heart, increasing levels of proteins thought to have beneficial cardiovascular effects (e.g. endothelial nitric oxide (NO) synthase (eNOS)) as well as those thought to have detrimental cardiovascular effects (e.g. type 1 angiotensin II (AngII) receptor (AT(1)R)). Ovariectomized Wistar rats consuming a high-sodium diet received one of four treatments (n=7 per group): group 1, placebo pellets; group 2, E(2) (0 x 5 mg/pellet, 21-day release); group 3, NOS inhibitor, N(omega)-nitro-L-arginine-methyl-ester (L-NAME; 40 mg/kg per day for 14 days) plus Ang II (0 x 225 mg/kg per day on days 11-14); group 4, E(2) plus L-NAME/Ang II. E(2) increased cardiac levels of estrogen receptors ESR1 and ESR2, an ESR-associated membrane protein caveolin-3, eNOS, and phosphorylated (p)eNOS, thus, exerting potentially beneficial cardiovascular effects on NO. However, E(2) also increased cardiac levels of proteins associated with cardiovascular injury and inflammation including, AT(1)R, protein kinase C delta (PRKCD), phosphorylated PRKC, and phosphorylated extracellular signal regulated kinase (pMAPK)3/1, plasminogen activator inhibitor-1 (PAI-1), osteopontin and ED-1, a monocyte/macrophage-specific protein. E(2) treatment led to similar protein changes in the hearts of L-NAME/Ang II-treated rats except that the increase in peNOS was prevented, and L-NAME/Ang II and E(2) had additive effects in increasing cardiac PRKCD and PAI-1. Thus, the highest levels of cardiac PAI-1 and PRKCD occurred in L-NAME/Ang II-treated rats receiving E(2). In summary, E(2) treatment increased cardiac expression of AT(1)R as well as the expression of pro-inflammatory and prothrombotic factors.
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Acute subarachnoid haemorrhage as a precipitant for takotsubo cardiomyopathy: a case report and discussion.
Int. J. Cardiol.
PUBLISHED: 07-08-2009
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Takotsubo cardiomyopathy is a recently recognised acute cardiac entity. It involves transient left ventricular apical ballooning, which is usually preceded by an episode of physiological or emotional stress. Its presentation may mimic acute myocardial infarction but there is no evidence of obstructive disease at coronary angiography. The aetiology of this condition has not been clearly defined, though a number of hypotheses have been put forward. Precipitating factors vary widely, including acute medical conditions and emotional stressors. We present a case of takotsubo cardiomyopathy precipitated by acute subarachnoid haemorrhage, the first report of this association in a Caucasian patient, and discuss the implications for clinicians involved in the management of such a case.
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Glycated albumin and direct low density lipoprotein cholesterol levels in type 2 diabetes mellitus.
Clin. Chim. Acta
PUBLISHED: 05-14-2009
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Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the utility of glycated albumin (GA) and direct LDL-C, 2 novel assay, as compared to HbA1c and calculated LDL-C, in evaluating diabetes control and lipid in a heterogeneous population and in specific subgroups of patients with type 2 diabetes mellitus.
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Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
, Sekar Kathiresan, Benjamin F Voight, Shaun Purcell, Kiran Musunuru, Diego Ardissino, Pier M Mannucci, Sonia Anand, James C Engert, Nilesh J Samani, Heribert Schunkert, Jeanette Erdmann, Muredach P Reilly, Daniel J Rader, Thomas Morgan, John A Spertus, Monika Stoll, Domenico Girelli, Pascal P McKeown, Chris C Patterson, David S Siscovick, Christopher J O'Donnell, Roberto Elosua, Leena Peltonen, Veikko Salomaa, Stephen M Schwartz, Olle Melander, David Altshuler, Pier Angelica Merlini, Carlo Berzuini, Luisa Bernardinelli, Flora Peyvandi, Marco Tubaro, Patrizia Celli, Maurizio Ferrario, Raffaela Fetiveau, Nicola Marziliano, Giorgio Casari, Michele Galli, Flavio Ribichini, Marco Rossi, Francesco Bernardi, Pietro Zonzin, Alberto Piazza, Jean Yee, Yechiel Friedlander, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Aki S Havulinna, Göran Berglund, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Marta Spreafico, Mark J Daly, James Nemesh, Joshua M Korn, Steven A McCarroll, Aarti Surti, Candace Guiducci, Lauren Gianniny, Daniel Mirel, Melissa Parkin, Noel Burtt, Stacey B Gabriel, John R Thompson, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, Alistair S Hall, Patrick Linsel-Nitschke, Wolfgang Lieb, Andreas Ziegler, Inke König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Anika Grosshennig, Michael Preuss, H-Erich Wichmann, Stefan Schreiber, Willem Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, Mingyao Li, Zhen Chen, Robert Wilensky, William Matthai, Atif Qasim, Hakon H Hakonarson, Joe Devaney, Mary-Susan Burnett, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent Mooser, Stephen E Epstein, Thomas Scheffold, Klaus Berger, Andreas Huge, Nicola Martinelli, Oliviero Olivieri, Roberto Corrocher, Pascal McKeown, Erdmann Erdmann, Inke R König, Hilma Holm, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Ron Do, Changchun Xie, David Siscovick.
Nat. Genet.
PUBLISHED: 01-16-2009
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We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
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The influence of sodium- and calcium-regulatory hormone interventions on adipocytokines in obesity and diabetes.
Metab. Clin. Exp.
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The renin-angiotensin-aldosterone system (RAAS), vitamin D, and parathyroid hormone have all been implicated as regulators of adipocytokines and inflammation. We evaluated human interventional study protocols to investigate whether controlled modulations of these calcium- and sodium-regulatory hormones could influence adipocytokines and inflammation in obesity and diabetes.
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Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake.
Age (Dordr)
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How interactions of an individuals genetic background and environmental factors, such as dietary salt intake, result in age-associated blood pressure elevation is largely unknown. Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation and modification of gene transcription. We have shown previously that hypertensive African-American minor allele carriers of the LSD1 single nucleotide polymorphism (rs587168) display blood pressure salt sensitivity. Our goal was to further examine the effects of LSD1 genotype variants on interactions between dietary salt intake, age, and blood pressure. We found that LSD1 single nucleotide polymorphism (rs7548692) predisposes to increasing salt sensitivity during aging in normotensive Caucasian subjects. Using a LSD1 heterozygous knockout mouse model, we compared blood pressure values on low (0.02 % Na(+)) vs. high (1.6 % Na(+)) salt intake. Our results demonstrate significantly increased blood pressure salt sensitivity in LSD1-deficient compared to wild-type animals with age, confirming our findings of salt sensitivity in humans. Elevated blood pressure in LSD1(+/-) mice is associated with total plasma volume expansion and altered renal Na(+) excretion. In summary, our human and animal studies demonstrate that LSD1 is a genetic factor that interacts with dietary salt intake modifying age-associated blood pressure increases and salt sensitivity through alteration of renal Na(+) handling.
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Effect of low dose mineralocorticoid receptor antagonist eplerenone on glucose and lipid metabolism in healthy adult males.
Metab. Clin. Exp.
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Mineralocorticoid Receptor (MR) activation is involved in blood pressure regulation and the pathogenesis of cardiovascular diseases, such as cardiac fibrosis, vascular inflammation and arterial aging. Recent investigations suggest a role for MR activation in metabolic dysregulation.
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Pelvic floor structure and function in women with vesicovaginal fistula.
J. Urol.
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Vesicovaginal fistula is a catastrophic event, especially in areas with poor peripartum care, where most occur. It is usually due to severely obstructed and protracted labor. We assumed that such patients would show evidence of abnormal levator function, eg due to denervation.
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Direct renin inhibition modulates insulin resistance in caveolin-1-deficient mice.
Metab. Clin. Exp.
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To test the hypothesis that aliskiren improves the metabolic phenotype in a genetic mouse model of the metabolic syndrome (the caveolin-1 (cav-1) knock out (KO) mouse).
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Nonmodulation as the mechanism for salt sensitivity of blood pressure in individuals with hypertension and type 2 diabetes mellitus.
J. Clin. Endocrinol. Metab.
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It is assumed that in individuals with type 2 diabetes mellitus (T2DM), blood pressure sensitivity to salt intake and the frequency of a low renin state are both increased compared with the nondiabetic population. However, studies supporting these assumptions may have been confounded by participant inclusion criteria, and study results may reflect target organ damage.
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The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression.
Psychoneuroendocrinology
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Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs).
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Different polymorphisms of the mineralocorticoid receptor gene are associated with either glucocorticoid or mineralocorticoid levels in hypertension.
J. Clin. Endocrinol. Metab.
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Both aldosterone and cortisol can activate the mineralocorticoid receptor (MR). Polymorphisms in the MR gene have been inconsistently shown to be associated with risk of hypertension and aldosterone and cortisol levels. The purpose of this project was to investigate the association of MR gene variants with serum aldosterone and a previously identified hypertension subgroup with higher urinary free cortisol (UFC) levels (high-mode UFC) in a rigorously phenotyped Caucasian hypertensive cohort.
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Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension.
Am. J. Hypertens.
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Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).
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Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, , James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josée Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noel P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Paré, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Asa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena González, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-Der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, José M Ordovás, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Sekar Kathiresan.
PLoS Genet.
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Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P?=?4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N?=?4,232 African Americans, N?=?1,776 Asians, and N?=?29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p?=?4.3×10(-3), n?=?22,044), increased triglycerides (p?=?2.6×10(-14), n?=?93,440), increased waist-to-hip ratio (p?=?1.8×10(-5), n?=?77,167), increased glucose two hours post oral glucose tolerance testing (p?=?4.4×10(-3), n?=?15,234), increased fasting insulin (p?=?0.015, n?=?48,238), but with lower in HDL-cholesterol concentrations (p?=?4.5×10(-13), n?=?96,748) and decreased BMI (p?=?1.4×10(-4), n?=?121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
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No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.
Robert A Scott, Audrey Y Chu, Niels Grarup, Alisa K Manning, Marie-France Hivert, Dmitry Shungin, Anke Tönjes, Ajay Yesupriya, Daniel Barnes, Nabila Bouatia-Naji, Nicole L Glazer, Anne U Jackson, Zoltan Kutalik, Vasiliki Lagou, Diana Marek, Laura J Rasmussen-Torvik, Heather M Stringham, Toshiko Tanaka, Mette Aadahl, Dan E Arking, Sven Bergmann, Eric Boerwinkle, Lori L Bonnycastle, Stefan R Bornstein, Eric Brunner, Suzannah J Bumpstead, Soren Brage, Olga D Carlson, Han Chen, Yii-Der Ida Chen, Peter S Chines, Francis S Collins, David J Couper, Elaine M Dennison, Nicole F Dowling, Josephine S Egan, Ulf Ekelund, Michael R Erdos, Nita G Forouhi, Caroline S Fox, Mark O Goodarzi, Jürgen Gräßler, Stefan Gustafsson, Göran Hallmans, Torben Hansen, Aroon Hingorani, John W Holloway, Frank B Hu, Bo Isomaa, Karen A Jameson, Ingegerd Johansson, Anna Jonsson, Torben Jørgensen, Mika Kivimäki, Peter Kovacs, Meena Kumari, Johanna Kuusisto, Markku Laakso, Cécile Lecoeur, Claire Levy-Marchal, Guo Li, Ruth J F Loos, Valeri Lyssenko, Michael Marmot, Pedro Marques-Vidal, Mario A Morken, Gabriele Müller, Kari E North, James S Pankow, Felicity Payne, Inga Prokopenko, Bruce M Psaty, Frida Renstrom, Ken Rice, Jerome I Rotter, Denis Rybin, Camilla H Sandholt, Avan A Sayer, Peter Shrader, Peter E H Schwarz, David S Siscovick, Alena Stančáková, Michael Stumvoll, Tanya M Teslovich, Gérard Waeber, Gordon H Williams, Daniel R Witte, Andrew R Wood, Weijia Xie, Michael Boehnke, Cyrus Cooper, Luigi Ferrucci, Philippe Froguel, Leif Groop, W H Linda Kao, Peter Vollenweider, Mark Walker, Richard M Watanabe, Oluf Pedersen, James B Meigs, Erik Ingelsson, Inês Barroso, Jose C Florez, Paul W Franks, Josée Dupuis, Nicholas J Wareham, Claudia Langenberg.
Diabetes
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Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (? = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (? = 0.06-0.12 mmol/allele, P ? 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ? 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
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Altered systemic hemodynamic and baroreflex response to angiotensin II in postural tachycardia syndrome.
Circ Arrhythm Electrophysiol
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Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls.
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A genome-wide association search for type 2 diabetes genes in African Americans.
Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, , Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michèle M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noel P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Straßburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M Van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stéphane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, André Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Gonçalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jérôme Delplanque, Annette C Fedson, Antje Fischer-Rosinský, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galán, Mark O Goodarzi, Jurgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesäniemi, Mika Kivimäki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polašek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Järvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek.
PLoS ONE
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African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n?=?550 independent loci) were genotyped in a replication cohort and 122 SNPs (n?=?98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P?=?7.0×10(-9), OR (95% CI)?=?0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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