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Find video protocols related to scientific articles indexed in Pubmed.
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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Reducing endoglin activity limits calcineurin and TRPC-6 expression and improves survival in a mouse model of right ventricular pressure overload.
J Am Heart Assoc
PUBLISHED: 07-13-2014
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Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-?1). TGF-?1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-?1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO.
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PDE5 inhibitor efficacy is estrogen dependent in female heart disease.
J. Clin. Invest.
PUBLISHED: 03-06-2014
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Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase I? (PKGI?). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from G?q-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGI?, indicating that PKGI? mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.
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The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice.
J. Am. Assoc. Lab. Anim. Sci.
PUBLISHED: 01-14-2014
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Minimizing and alleviating pain and distress in laboratory mice without compromising the methodologic integrity of research is a crucial goal. However, current methods for welfare assessment in mice are not well suited to cageside checks. In the present study, we developed a simple assessment tool-the time-to-integrate-to-nest test (TINT)-and evaluated its ability to identify mice with compromised welfare. To conduct the TINT, a nominal amount of nesting material is added to a mouse cage, and the nesting behaviors that occur immediately thereafter are observed. The TINT yields a positive result when a mouse integrates the new nesting material into the main nest site within 10 min; failure to interact with the nesting material is defined as a negative TINT. Our first experiment examined whether genetic background and sex are associated with differences in the likelihood of a positive TINT in unmanipulated mice. A significant effect related to mouse strain was found: C3H/HeNCrl had the lowest positive TINT rate among the 10 strains evaluated. A second experiment assessed whether results of the TINT would be altered after a painful surgical procedure, such as carotid artery injury. Despite all mice having received buprenorphine as analgesia at the time of surgery, significantly more mice had a negative TINT for 2 d after surgery than before surgery. Based on the results of the current study, additional work is needed to specifically validate the TINT in injured and noninjured subjects.
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Lipoprotein-associated phospholipase A2, a novel cardiovascular inflammatory marker, in HIV-infected patients.
Clin. Infect. Dis.
PUBLISHED: 01-02-2014
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Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging biomarker of cardiovascular disease. This study was conducted to describe the distribution of Lp-PLA2 in a cohort of human immunodeficiency virus (HIV)-infected adults and to determine associations between Lp-PLA2, cardiometabolic risk factors, and subclinical atherosclerosis in this population.
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??T Cells Are Prevalent in the Proximal Aorta and Drive Nascent Atherosclerotic Lesion Progression and Neutrophilia in Hypercholesterolemic Mice.
PLoS ONE
PUBLISHED: 01-01-2014
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Unique innate immunity-linked ??T cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether ??T cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that ??T cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wild-type mice during early atherogenesis, particularly in the aortic root and arch, where they comprised most of the T cells and lesion progression is most rapid. ??T cells infiltrated intimal lesions in ApoE KO mice, but only the adventitia in wild-type mice, and were more prevalent than CD4+ T cells in early nascent lesions, as evaluated by en face confocal microscopy. These aortic ??T cells produced IL-17, but not IFN-?, analyzed by ex vivo FACS. Furthermore, aortic arch lipid accumulation correlated strongly with abundance of IL-17-expressing splenic ??T cells in individual ApoE KO mice. To investigate the role of these ??T cells in early atherogenesis, we analyzed ApoE/??T double knockout (DKO) compared to ApoE KO mice. We observed reduced early intimal lipid accumulation at sites of nascent lesion formation, both in chow-fed (by 40%) and Western diet-fed (by 44%) ApoE/??T DKO mice. In addition, circulating neutrophils were drastically reduced in these DKO mice on Western diet, while expansion of inflammatory monocytes and splenic Th1 or Th17 lymphocytes was not affected. These data reveal, for the first time, a pathogenic role of ??T cells in early atherogenesis in ApoE KO mice, by mechanisms likely to involve their IL-17 production and induction of neutrophilia. Targeting ??T cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.
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Vascular reactivity screen of Chinese medicine danhong injection identifies Danshensu as a NO-independent but PGI2-mediated relaxation factor.
J. Cardiovasc. Pharmacol.
PUBLISHED: 08-08-2013
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Danhong injection (DHI) is the most prescribed injection form of Chinese medicine for the treatment of cardiovascular diseases such as atherosclerosis, angina pectoris, and stroke in China. However, its active components and action mechanisms remain poorly defined. We hypothesized that DHI contains active components that could prevent and restore endothelial dysfunction by improving vascular relaxation activity. DHI increased vasorelaxation in vivo and ex vivo of rat aortas. Vascular reactivity screen identified that danshensu was the major relaxation factor in DHI. DHI-mediated endothelial-dependent vasorelaxation was independent on nitric oxide/endothelial nitric oxide synthase but was via prostacyclin pathway by increasing cyclooxygenase (COX)-2 gene expression and prostacyclin production. Our results revealed a previously unknown endothelium-dependent vasorelaxation mechanism by danshensu and together with previously reported activity on ion channels of vascular smooth muscle cells, demonstrated that its dual actions contribute to a multicomponent Chinese herbal medicine that synergistically targets different pathways to achieve its well-documented cardiovascular protective effects.
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High-density lipoproteins: a consensus statement from the National Lipid Association.
J Clin Lipidol
PUBLISHED: 07-29-2013
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For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the "HDL hypothesis" have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panels conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function.
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Mechanically unloading the left ventricle before coronary reperfusion reduces left ventricular wall stress and myocardial infarct size.
Circulation
PUBLISHED: 06-13-2013
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Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI.
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Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 06-06-2013
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The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases, such as atherosclerosis and restenosis, after percutaneous coronary intervention. Many studies have shown that estrogen inhibits VSMC proliferation in response to vascular injury in the mouse carotid injury model. However, the mechanisms that mediate these effects remain unclear. Here, we investigated the mechanisms by which estrogen inhibits VSMC proliferation.
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Mutation of the protein kinase I alpha leucine zipper domain produces hypertension and progressive left ventricular hypertrophy: a novel mouse model of age-dependent hypertensive heart disease.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 05-08-2013
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Hypertensive heart disease causes significant mortality in older patients, yet there is an incomplete understanding of molecular mechanisms that regulate age-dependent hypertensive left ventricular hypertrophy (LVH). Therefore, we tested the hypothesis that the cGMP-dependent protein kinase G I alpha (PKGI?) attenuates hypertensive LVH by evaluating the cardiac phenotype in mice with selective mutations of the PKGI? leucine zipper domain. These leucine zipper mutant (LZM) mice develop basal hypertension. Compared with wild-type controls, 8-month-old adult LZM mice developed increased left ventricular end-diastolic pressure but without frank LVH. In advanced age (15 months), the LZM mice developed overt pathological LVH. These findings reveal a role of PKGI? in normally attenuating hypertensive LVH. Therefore, mutation of the PKGI? LZ domain produces a clinically relevant model for hypertensive heart disease of aging.
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Racial differences in central hemodynamic burden in men with HIV: preliminary findings.
Ethn Dis
PUBLISHED: 03-28-2013
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African Americans infected with HIV are almost 3 times more likely to die from cardiovascular disease (CVD) than their White HIV-infected counterparts. The purpose of this study was to examine racial differences in novel measures of vascular function and CVD risk in African American and White men infected with HIV.
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Biventricular remodeling in murine models of right ventricular pressure overload.
PLoS ONE
PUBLISHED: 01-01-2013
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Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGF?1).
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Peripheral augmentation index as a biomarker of vascular aging: an invasive hemodynamics approach.
Eur. J. Appl. Physiol.
PUBLISHED: 08-12-2011
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We compared two measures of vascular function obtained from digital volume waveforms with measures of target organ damage and novel invasive measures of vascular function as they relate to vascular aging. Aortic pulse pressure amplification, pulsatility, form factor and extent of coronary atherosclerosis (modified Gensini score) were obtained invasively in 59 patients undergoing left heart catheterization. Digital volume waveforms were captured via peripheral arterial tone (PAT) and used to derive augmentation index (AIx) and the pulse wave amplitude-reactive hyperemia index (PWA-RHI). AIx was associated with age (r = 0.50, p < 0.05) and aortic pulsatility (r = 0.45, p < 0.05) and inversely associated with estimated glomerular filtration rate (-0.29, p < 0.05) aortic pulse pressure amplification (r = -0.28, p < 0.05) and aortic form factor (r = -0.38, p < 0.05). AIx was slightly higher in patients with left ventricular hypertrophy (LVH) versus those without left ventricular hypertrophy (30 vs. 14%, p = 0.058). There was no association between AIx and Gensini score. PWA-RHI was not associated with age, estimated glomerular filtration rate or invasive vascular parameters and did not differ in patients with versus without LVH (p = ns). PWA-RHI was inversely associated with Gensini score (r = -0.32, p < 0.05). AIx derived from PAT is correlated with age-associated changes in vascular function and target organ damage but not coronary atherosclerotic burden. PWA-RHI is associated with coronary atherosclerotic burden but is not associated with target organ damage or other measures of vascular aging assessed in this study. Each parameter provides distinct insight into systemic vascular aging and target organ damage.
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Endothelial function and soluble endoglin in smokers with heart failure.
Clin Cardiol
PUBLISHED: 08-09-2011
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Although cigarette smoking is a risk factor for heart failure (HF), smokers with HF have lower mortality rates during/following hospitalization compared to nonsmokers. We examined vascular endothelial function in chronic smokers and nonsmokers with HF as it relates to this smokers paradox.
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Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3.
BMC Biochem.
PUBLISHED: 03-25-2011
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Striatin, a putative protein phosphatase 2A (PP2A) B-type regulatory subunit, is a multi-domain scaffolding protein that has recently been linked to several diseases including cerebral cavernous malformation (CCM), which causes symptoms ranging from headaches to stroke. Striatin association with the PP2A A/C (structural subunit/catalytic subunit) heterodimer alters PP2A substrate specificity, but targets and roles of striatin-associated PP2A are not known. In addition to binding the PP2A A/C heterodimer to form a PP2A holoenzyme, striatin associates with cerebral cavernous malformation 3 (CCM3) protein, the mammalian Mps one binder (MOB) homolog, Mob3/phocein, the mammalian sterile 20-like (Mst) kinases, Mst3, Mst4 and STK25, and several other proteins to form a large signaling complex. Little is known about the molecular architecture of the striatin complex and the regulation of these sterile 20-like kinases.
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Augmentation index derived from peripheral arterial tonometry correlates with cardiovascular risk factors.
Cardiol Res Pract
PUBLISHED: 03-17-2011
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Background. Augmentation index (AIx) is traditionally obtained from pressure waveforms via arterial applanation tonometry. We sought to evaluate the association between AIx obtained from peripheral arterial tonometry (PAT) with cardiovascular risk factors (CRF) and coronary artery disease (CAD). Methods. 186 patients were enrolled in the study. The presence or absence of CRFs and CAD was assessed in each subject. AIx was calculated by an automated algorithm averaging pulse wave amplitude data obtained via PAT. Central blood pressures were assessed in a subset of patients undergoing clinically indicated cardiac catheterization. Results. An association was observed between AIx and age, heart rate, systolic blood pressure, mean arterial pressure, pulse pressure, body weight and body mass index. AIx was significantly lower in patients with <3 CRFs compared to those with >5 CRFs ( P = .02). CAD+ patients had significantly higher AIx compared to CAD- patients ( P = .008). Area under the ROC curve was 0.604 (P < .01). In patients undergoing cardiac catheterization, after adjusting for age, height and heart rate, AIx was a significant predictor of aortic systolic and pulse pressures (P < .05) Conclusion. AIx derived from PAT correlates with cardiac risk factors and CAD. It may be a useful measure of assessing overall risk for coronary artery disease.
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Peripheral augmentation index and vascular inflammation in autosomal dominant polycystic kidney disease.
Nephrol. Dial. Transplant.
PUBLISHED: 02-03-2011
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Cardiovascular disease is the leading cause of premature mortality in autosomal dominant polycystic kidney disease (ADPKD). We examined peripheral augmentation index (AIx) as a measure of systemic vascular function and circulating markers of vascular inflammation in patients with ADPKD.
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Effect of atenolol vs metoprolol succinate on vascular function in patients with hypertension.
Clin Cardiol
PUBLISHED: 01-25-2011
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We evaluated the effect of atenolol vs metoprolol succinate on vascular function in patients with essential hypertension.
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Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk.
Ann. Intern. Med.
PUBLISHED: 12-22-2010
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Low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk for myocardial infarction (MI). Although statins reduce the risk for MI, most cardiovascular events still occur despite statin treatment.
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Elevated soluble fms-like tyrosine kinase-1 levels in acute coronary occlusion.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 11-11-2010
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Early recognition of an acute coronary occlusion (ACO) improves clinical outcomes. Soluble fms-like tyrosine kinase-1 (sFLT1) is an endothelium-derived protein induced by hypoxia. We tested whether sFLT1 levels are elevated in ACO.
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Endothelial progenitor cells delivered into the pericardial space incorporate into areas of ischemic myocardium.
Cardiovasc Revasc Med
PUBLISHED: 10-12-2010
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Our objective was to determine whether autologous endothelial progenitor cells (EPCs) delivered into the pericardial space will migrate to and incorporate into ischemic myocardium in a porcine model.
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Renal actions of RGS2 control blood pressure.
J. Am. Soc. Nephrol.
PUBLISHED: 09-16-2010
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G protein-coupled receptors (GPCRs) have key roles in cardiovascular regulation and are important targets for the treatment of hypertension. GTPase-activating proteins, such as RGS2, modulate downstream signaling by GPCRs. RGS2 displays regulatory selectivity for the G?q subclass of G proteins, and mice lacking RGS2 develop hypertension through incompletely understood mechanisms. Using total body RGS2-deficient mice, we used a kidney crosstransplantation strategy to examine separately the contributions of RGS2 actions in the kidney from those in extrarenal tissues with regard to BP regulation. Loss of renal RGS2 was sufficient to cause hypertension, whereas the absence of RGS2 from all extrarenal tissues including the peripheral vasculature did not significantly alter BP. Accordingly, these results suggest that RGS2 acts within the kidney to modulate BP and prevent hypertension. These data support a critical role for the renal epithelium and/or vasculature as the final determinants of the intra-arterial pressure in hypertension.
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Relation of pulse pressure to blood pressure response to exercise in patients with hypertrophic cardiomyopathy.
Am. J. Cardiol.
PUBLISHED: 08-13-2010
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Almost one third of patients with hypertrophic cardiomyopathy (HC) will have an abnormal blood pressure response (ABPR) to exercise, and this has been associated with a greater risk of sudden cardiac death. In the present study, we examined the association between the steady (mean arterial pressure) and pulsatile (pulse pressure) blood pressure components as they relate to ABPR in patients with HC (n = 70). All patients completed a standard Bruce protocol during symptom-limited stress testing with concurrent hemodynamic measurements. Pulse pressure (PP) was significantly greater in patients with HC with an ABPR (n = 19) than in the patients with HC without an ABPR to exercise (p <0.05). According to binary logistic regression analysis, PP at rest was a significant predictor of ABPR in patients with HC (p <0.05). Mean arterial pressure was not significantly different between the 2 groups, nor was it a predictor of an ABPR in the presence of HC. Those within the greatest tertile of PP at rest were 4.8 times more likely to have an ABPR than those within the lowest PP tertile (95% confidence interval 1.24 to 18.2, p <0.05). In conclusion, elevations in PP at rest might identify patients with HC at a greater risk of having an ABPR during exercise.
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Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy.
J. Am. Coll. Cardiol.
PUBLISHED: 06-29-2010
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We sought to examine the relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of the development of cancer in large randomized controlled trials (RCTs) of lipid-altering interventions.
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Niacins role in the statin era.
Expert Opin Pharmacother
PUBLISHED: 06-24-2010
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The combination use of niacin and HMG Co-A reductases (statins) is increasing. While statin therapy reduces the risk of adverse cardiovascular events, additional therapies are needed to decrease event rates further. High-density lipoprotein cholesterol (HDL-C) is of interest as a potential therapeutic target as epidemiologic evidence demonstrates that low HDL-C is a strong predictor of incident coronary events. Niacin is the most effective agent available at present to increase HDL-C.
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Rapid progress for non-nuclear estrogen receptor signaling.
J. Clin. Invest.
PUBLISHED: 06-23-2010
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Estrogen receptors are best known as ligand-activated transcription factors that regulate vascular cell gene expression. For many years now, a rapid signaling pathway mediated by cell membrane-associated estrogen receptors also has been recognized, but the physiological relevance of this pathway has remained unclear. In this issue of the JCI, Chambliss et al. provide new data to indicate that activation of non-nuclear estrogen receptor signaling regulates processes central to cardiovascular health and disease. These investigators show that an estrogen-dendrimer conjugate (EDC), which activates estrogen receptors but remains non-nuclear, stimulates vascular EC migration in vitro and protects against vascular injury in vivo. They show further that the vascular benefits of EDC in vivo occur selectively in the vasculature, without stimulating the uterus or enhancing growth of breast cancer xenografts. Taken together, these findings indicate that activation of non-nuclear estrogen receptor signaling regulates vascular events of physiological relevance and suggest that translation of these findings into clinically relevant therapeutic interventions is a logical next goal.
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Postmenopausal hormone therapy: an Endocrine Society scientific statement.
J. Clin. Endocrinol. Metab.
PUBLISHED: 06-21-2010
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Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.
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Elevated augmentation index derived from peripheral arterial tonometry is associated with abnormal ventricular-vascular coupling.
Clin Physiol Funct Imaging
PUBLISHED: 06-10-2010
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Although typically derived from the contour of arterial pressure waveform, augmentation index (AIx) may also be derived from the digital pulse volume waveform using finger plethysmography (peripheral arterial tonometry, PAT). Little is known regarding the physiologic correlates of AIx derived from PAT. In this study, we investigated the relation of PAT-AIx with measures of ventricular-vascular coupling.
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Usefulness of soluble endoglin as a noninvasive measure of left ventricular filling pressure in heart failure.
Am. J. Cardiol.
PUBLISHED: 05-10-2010
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Progressive left ventricular (LV) dysfunction induces expression of the cytokine transforming growth factor-?1. Endoglin (CD105) is a transforming growth factor-?1 co-receptor that is released into the circulation as soluble endoglin (sEng). The objective of the present study was to assess the serum levels of sEng in patients with heart failure and to identify the predictive value of sEng for detecting elevated left ventricular end-diastolic pressures (LVEDPs). We measured the sEng levels in 82 consecutive patients with suspected LV dysfunction referred for determination of left heart filling pressures using cardiac catheterization. Among these subjects, the sEng levels correlated with the LVEDP (R = 0.689; p <0.0001), irrespective of the LV ejection fraction. Using a receiving operating characteristic curve, the sEng levels predicted an LVEDP of ?16 mm Hg with an area under the curve of 0.85, exceeding the measured area under the curves for both atrial and brain natriuretic peptide, currently used biomarkers for heart failure diagnosis (atrial natriuretic peptide 0.68 and brain natriuretic peptide 0.65; p <0.01 vs sEng). In 10 subjects receiving medical therapy guided by invasive hemodynamic monitoring for heart failure, decreased a pulmonary capillary wedge pressure was associated with a reduced sEng level (R = 0.75, p = 0.008). Finally, compared to 25 healthy controls, the sEng levels were elevated in subjects with suspected LV dysfunction (3,589 ± 588 vs 4,257 ± 966 pg/ml, respectively, p <0.005) and correlated directly with the New York Heart Association class (R = 0.501, p<0.001). In conclusion, circulating levels of sEng are elevated in patients with increased LVEDP and New York Heart Association class, irrespective of the LV ejection fraction. sEng levels also decreased in association with a reduced cardiac filling pressure after diuresis. These findings have identified circulating sEng as a sensitive measure of elevated left heart filling pressures.
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Nonoptimal high-density lipoprotein cholesterol levels are highly prevalent in patients presenting with acute coronary syndromes and well-controlled low-density lipoprotein cholesterol levels.
J Clin Lipidol
PUBLISHED: 04-02-2010
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Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for coronary artery disease. For this study, nonoptimal HDL-C is defined as less than 40 mg/dL for male patients and less than 50 mg/dL for female patients. Even when low-density lipoprotein cholesterol (LDL-C) and non-HDL-C goals are met, significant risk for subsequent cardiovascular events remains in patients with acute coronary syndrome (ACS).
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Endothelium-dependent vasodilation is associated with exercise capacity in smokers and non-smokers.
Vasc Med
PUBLISHED: 03-18-2010
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Smoking is an established cardiovascular risk factor that impairs endothelial function and reduces exercise capacity. Peripheral vascular endothelial function correlates with exercise capacity, but whether this association prevails in smokers is unknown. The purpose of this investigation was to examine the association between endothelial function and exercise capacity in chronic smokers and non-smoking controls. Brachial artery flow-mediated dilation (FMD, endothelium-dependent) following 5 minutes of upper arm occlusion was compared in 26 smokers (age 58 +/- 2 years; 15 female; BMI (body mass index) = 28 +/- 1) and 39 non-smokers (age 58 +/- 2 years; 24 female; BMI = 28 +/- 1) using ultrasound. Exercise treadmill time (ETT) was recorded from a standard Bruce protocol during symptom limited stress testing. There was found to be a significant positive association between FMD and ETT in smokers (r = 0.60, p < 0.05) and non-smokers (r = 0.28, p < 0.05). FMD was significantly lower in smokers versus non-smokers (8.9 +/- 0.9 vs 12.6 +/- 0.7%, p < 0.05). ETT was significantly lower in smokers (425 +/- 35 seconds) versus non-smokers (522 +/- 25 seconds, p < 0.05). After adjusting for FMD, there were no longer group differences in ETT. When patients were matched according to FMD, there were no differences in ETT between smokers and non-smokers. In conclusion, peripheral endothelial dysfunction is a correlate of low exercise capacity in smokers and non-smokers alike. Future research is needed to examine if improving endothelial function will lead to concomitant increases in exercise capacity in chronic smokers.
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Peripheral arterial tonometry for risk stratification in men with coronary artery disease.
Clin Cardiol
PUBLISHED: 02-27-2010
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Coronary artery disease (CAD) risk is not fully revealed by traditional risk factors. Identification of a simple, noninvasive tool that allows for detection of high-risk CAD patients and can be applied in large populations and clinical settings would prove valuable.
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Differential effects of statins (pravastatin or simvastatin) on ventricular ectopic complexes: Galpha(i2), a possible molecular marker for ventricular irritability.
Am. J. Cardiol.
PUBLISHED: 02-20-2010
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Retrospective studies suggest that statins might exert an antiarrhythmic effect on the heart. The mechanism of this effect is unclear. Parasympathetic stimulation of the heart has been shown to protect against ventricular arrhythmias. The goal of this study was to determine the effect of statins on ventricular arrhythmias and its correlation with changes in parasympathetic responsiveness and Galpha(i2) expression. Patients were randomized to pravastatin and simvastatin in a double-blind crossover design. Ventricular arrhythmias were determined by analysis of 24-hour Holter recordings. Spectral RR interval analysis of Holter studies determined peak high-frequency power fraction, which reflects parasympathetic modulation of heart rate. Expression of Galpha(i2), a molecular component of the parasympathetic response pathway, was determined by Western blots of patients lymphocytes. Pravastatin treatment decreased the incidence of ventricular premature complexes by 22.5 + or - 3.4% (n = 20, p <0.05), couplets, and runs of 3 to 6 beats of nonsustained ventricular tachycardia from 9.8 + or - 2.67 to 3.9 + or - 1.25 events/patient/24 hours (n = 12, p <0.05). Pravastatin increased peak high-frequency fraction by 29.8 + or - 4.3% (n = 33, p <0.001), while Galpha(i2) expression increased by 51.3 + or - 22.5% (n = 21, p <0.05). Effects of simvastatin on ventricular premature complexes and nonsustained ventricular tachycardia were not significant. Relative changes in couplets and nonsustained ventricular tachycardia in pravastatin-treated patients correlated negatively with changes in Galpha(i2) and high-frequency fraction (rho = -0.588 and rho = -0.763, respectively, n = 12, p <0.05). In conclusion, these data suggest that pravastatin might decrease cardiac irritability via an increase in parasympathetic responsiveness and that changes in Galpha(i2) expression might serve as a molecular marker for this effect, which might play a role in the molecular mechanism of the antiarrhythmic effect of statins.
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Peripheral vascular endothelial function in patients with hypertrophic cardiomyopathy.
Am. J. Cardiol.
PUBLISHED: 01-28-2010
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Patients with hypertrophic cardiomyopathy (HC) have coronary microvascular dysfunction, which is an independent predictor of adverse left ventricular remodeling, systolic dysfunction, and mortality in these patients. Whether these defects in vasomotor function are localized to the coronary arteries or whether systemic vasomotor dysfunction is present in patients with HC has not yet been adequately examined. The aim of this study was to test the hypothesis that patients with HC have altered peripheral vascular endothelial function. Subjects without coronary artery disease (CAD) and those with CAD served as negative and positive controls, respectively. Conduit artery endothelium-dependent vasomotion was assessed with ultrasound by measuring flow-mediated dilation of the brachial artery. Flow-mediated dilation was lower in patients with HC compared with those without CAD (p <0.05) but was similar in patients with CAD (p = NS). In conclusion, vasomotor dysfunction in HC is not restricted to the coronary vasculature. Patients with HC have impaired peripheral conduit vessel endothelial function, and the magnitude of impairment is similar to that seen in older patients with advanced CAD.
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Pulse wave amplitude is associated with brachial artery diameter: implications for gender differences in microvascular function.
Vasc Med
PUBLISHED: 12-21-2009
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The ratio of pulse wave amplitude (PWA) during reactive hyperemia compared to baseline as measured by peripheral arterial tonometry (PAT) is a non-invasive measure of microvascular endothelial function referred to as the pulse wave amplitude reactive hyperemia index (PWA-RHI). Whether upstream conduit vessel structure may affect downstream resistance vessel PWA has not been clearly examined. We tested the hypothesis that digital PWA is influenced by brachial artery diameter (BAD) and that this association would influence comparison of PWA-RHI between genders. Measures of vascular structure and microvascular function were carried out in 115 patients varying in cardiovascular risk profiles (average age 57 years, male n = 79, CAD n = 43). PWA was assessed using plethysmography at baseline and following 5 minutes of brachial artery occlusion. BAD was assessed using high-resolution ultrasonography. Results : There was a negative association between BAD and PWA-RHI ( r = -0.34, p < 0.05). Women had greater PWA-RHI and smaller BAD compared with men (p < 0.05). When co-varying for BAD, there were no longer gender differences in PWA-RHI. Moreover, when a sub-group of men and women without CAD (n = 40), matched for BAD, were examined, there were no gender differences in PWA-RHI. In conclusion, PWA-RHI obtained from PAT is associated with BAD. Studies examining gender differences in microvascular endothelial function with PAT may need to correct for BAD as a potential confounder.
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Modestly overweight women have vascular endothelial dysfunction.
Clin Cardiol
PUBLISHED: 05-20-2009
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Vascular endothelial dysfunction occurs early in the atherosclerotic process and is predictive of cardiovascular prognosis. However, the association between specific cardiovascular risk factors and endothelial dysfunction in women has not been well characterized. This study examined the relationship between endothelial dysfunction and cardiovascular risk factors (body mass index [BMI] >or= 25 kg/m(2), current smoking, age, diabetes, hypertension, hypercholesterolemia, and family history of early coronary heart disease) in a population of women that included those already being treated for risk factors.
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Role of SREBP-1 in the development of parasympathetic dysfunction in the hearts of type 1 diabetic Akita mice.
Circ. Res.
PUBLISHED: 05-07-2009
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Diabetic autonomic neuropathy (DAN), a major complication of diabetes mellitus, is characterized, in part, by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K+ current, I(KAch), via a (GIRK1)2/(GIRK4)2 K+ channel. Sterol regulatory element binding protein-1 (SREBP-1) is a lipid-sensitive transcription factor.
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The relationship of statins to rhabdomyolysis, malignancy, and hepatic toxicity: evidence from clinical trials.
Curr Atheroscler Rep
PUBLISHED: 02-21-2009
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3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are among the most commonly prescribed and studied drugs in modern medicine. Their proven benefit in prevention of cardiovascular events is driven by their ability to markedly reduce low-density lipoprotein cholesterol (LDL-C). Recent analyses have provided insight into the relationship between statin-induced reductions in LDL-C and risk of rhabdomyolysis, liver toxicity, and cancer. Risk of statin-associated elevated liver enzymes and rhabdomyolysis is not related to the magnitude of LDL-C lowering. Instead, drug- and dose-specific effects of statins are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, although there is an inverse association between LDL-C and cancer risk in both statin-treated and comparable control cohorts, statin therapy, despite significantly reducing LDL-C, is not associated with an increased risk of cancer.
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Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation.
Circ. Res.
PUBLISHED: 02-13-2009
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Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a critical role in the development of pathological hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17beta-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 weeks, mice underwent physiological evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathological LV and cardiomyocyte growth.
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Ezetimibe, and the combination of ezetimibe/simvastatin, and risk of cancer: A post-marketing analysis.
J Clin Lipidol
PUBLISHED: 02-03-2009
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In the recently reported Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, the combination of ezetimibe/simvastatin (E/S) was associated with a significantly increased risk of cancer compared to placebo, causing widespread public concern.
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Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD.
J Clin Lipidol
PUBLISHED: 02-01-2009
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The importance of the number of circulating low-density lipoprotein (LDL) cholesterol particles, in addition to total LDL level, has been increasingly recognized. The effects of extended-release niacin (ERN) on LDL particle numbers have not been studied.
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Protein kinase g i? inhibits pressure overload-induced cardiac remodeling and is required for the cardioprotective effect of sildenafil in vivo.
J Am Heart Assoc
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Cyclic GMP (cGMP) signaling attenuates cardiac remodeling, but it is unclear which cGMP effectors mediate these effects and thus might serve as novel therapeutic targets. Therefore, we tested whether the cGMP downstream effector, cGMP-dependent protein kinase G I? (PKGI?), attenuates pressure overload-induced remodeling in vivo.
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Emerging evidence of the importance of rapid, non-nuclear estrogen receptor signaling in the cardiovascular system.
Steroids
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Estrogen receptors are classically known as ligand-activated transcription factors that regulate gene transcription in cells in response to hormone binding. In addition to this "genomic" signaling pathway, a "rapid, non-nuclear" signaling pathway mediated by cell membrane-associated estrogen receptors also has been recognized. Although for many years there was little evidence to support any physiological relevance of rapid-signaling, very recently evidence has been accumulating supporting the importance of the rapid, non-nuclear signaling as potentially critical for the protective effects of estrogen in the cardiovascular system. Better understanding of the rapid, non-nuclear signaling potentially provides an opportunity to design "pathway-specific" selective estrogen receptor modulators capable of differentially regulating non-nuclear vs. genomic effects that may prove useful ultimately as specific therapies for cardiovascular diseases.
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The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression.
J. Am. Coll. Cardiol.
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This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.
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Estrogen receptor-mediated regulation of microRNA inhibits proliferation of vascular smooth muscle cells.
Arterioscler. Thromb. Vasc. Biol.
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Estradiol (E2) regulates gene transcription by activating estrogen receptor-? and estrogen receptor-?. Many of the genes regulated by E2 via estrogen receptors are repressed, yet the molecular mechanisms that mediate E2-induced gene repression are currently unknown. We hypothesized that E2, acting through estrogen receptors, regulates expression of microRNAs (miRs) leading to repression of expression of specific target genes.
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Direct binding and regulation of RhoA protein by cyclic GMP-dependent protein kinase I?.
J. Biol. Chem.
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Vascular smooth muscle cell (VSMC) tone is regulated by the state of myosin light chain (MLC) phosphorylation, which is in turn regulated by the balance between MLC kinase and MLC phosphatase (MLCP) activities. RhoA activates Rho kinase, which phosphorylates the regulatory subunit of MLC phosphatase, thereby inhibiting MLC phosphatase activity and increasing contraction and vascular tone. Nitric oxide is an important mediator of VSMC relaxation and vasodilation, which acts by increasing cyclic GMP (cGMP) levels in VSMC, thereby activating cGMP-dependent protein kinase I? (PKGI?). PKGI is known to phosphorylate Rho kinase, preventing Rho-mediated inhibition of MLC phosphatase, promoting vasorelaxation, although the molecular mechanisms that mediate this are unclear. Here we identify RhoA as a target of activated PKGI? and show further that PKGI? binds directly to RhoA, inhibiting its activation and translocation. In protein pulldown and immunoprecipitation experiments, binding of RhoA and PKGI? was demonstrated via a direct interaction between the amino terminus of RhoA (residues 1-44), containing the switch I domain of RhoA, and the amino terminus of PKGI? (residues 1-59), which includes a leucine zipper heptad repeat motif. Affinity assays using cGMP-immobilized agarose showed that only activated PKGI? binds RhoA, and a leucine zipper mutant PKGI? was unable to bind RhoA even if activated. Furthermore, a catalytically inactive mutant of PKGI? bound RhoA but did not prevent RhoA activation and translocation. Collectively, these results support that RhoA is a PKGI? target and that direct binding of activated PKGI? to RhoA is central to cGMP-mediated inhibition of the VSMC Rho kinase contractile pathway.
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Rapid estrogen receptor signaling is essential for the protective effects of estrogen against vascular injury.
Circulation
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Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which, when bound to estrogen, can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a rapid nonnuclear signaling cascade. However, the biological significance of this rapid signaling pathway has been unclear.
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Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice.
J. Thorac. Cardiovasc. Surg.
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Vein graft failure rates resulting from adverse graft remodeling remain high with no effective therapy. The mineralocorticoid receptor (MR) plays a role in pathologic arterial remodeling. We demonstrated recently that the MR is upregulated in venous tissues after grafting and hypothesized that MR inhibition would reduce vein graft remodeling.
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Cell surface estrogen receptor alpha is upregulated during subchronic metabolic stress and inhibits neuronal cell degeneration.
PLoS ONE
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In addition to the classical nuclear estrogen receptor, the expression of non-nuclear estrogen receptors localized to the cell surface membrane (mER) has recently been demonstrated. Estrogen and its receptors have been implicated in the development or progression of numerous neurodegenerative disorders. Furthermore, the pathogenesis of these diseases has been associated with disturbances of two key cellular programs: apoptosis and autophagy. An excess of apoptosis or a defect in autophagy has been implicated in neurodegeneration. The aim of this study was to clarify the role of ER in determining neuronal cell fate and the possible implication of these receptors in regulating either apoptosis or autophagy. The human neuronal cell line SH-SY5Y and mouse neuronal cells in primary culture were thus exposed to chronic minimal peroxide treatment (CMP), a form of subcytotoxic minimal chronic stress previously that mimics multiple aspects of long-term cell stress and represents a limited molecular proxy for neurodegenerative processes. We actually found that either E2 or E2-bovine serum albumin construct (E2BSA, i.e. a non-permeant form of E2) was capable of modulating intracellular cell signals and regulating cell survival and death. In particular, under CMP, the up-regulation of mER?, but not mER?, was associated with functional signals (ERK phosphorylation and p38 dephosphorylation) compatible with autophagic cytoprotection triggering and leading to cell survival. The mER? trafficking appeared to be independent of the microfilament system cytoskeletal network but was seemingly associated with microtubular apparatus network, i.e., to MAP2 molecular chaperone. Importantly, antioxidant treatments, administration of siRNA to ER?, or the presence of antagonist of ER? hindered these events. These results support that the surface expression of mER? plays a pivotal role in determining cell fate, and that ligand-induced activation of mER signalling exerts a powerful cell-survival signal. These results shed new light on the pathogenetic mechanisms leading to neuronal cell degeneration.
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Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.
Circulation
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Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-?1 (TGF?1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a coreceptor for TGF?1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure.
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Distinct effects of unfractionated heparin versus bivalirudin on circulating angiogenic peptides.
PLoS ONE
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Human studies of therapeutic angiogenesis, stem-cell, and progenitor-cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied.
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