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Find video protocols related to scientific articles indexed in Pubmed.
Intermittent cold stress enhances features of atherosclerotic plaque instability in apolipoprotein E?deficient mice.
Mol Med Rep
PUBLISHED: 08-07-2014
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The cold weather is associated with an increased occurrence of acute coronary events. However, the mechanisms underlying cold?induced myocardial infarctions have not yet been fully elucidated. In the present study, 20 male, eight week?old, apolipoprotein E (ApoE)?deficient mice were subjected to either control conditions or intermittent cold exposure for eight weeks. Mice in the cold group were placed in a cold room at 4?C for 4 h per day, while the mice in the control group were kept in a room at 24?C. Cold?exposed mice did not significantly differ from control mice in body weight, fasting glucose concentration and plasma lipid levels, including triglyceride, total cholesterol, low?density lipoprotein and high?density lipoprotein. The hematoxylin and eosin?stained sections of the aortic root demonstrated increased plaque size in the cold group compared with the control group (P<0.01). Furthermore, cold?treated mice exhibited significantly decreased plaque collagen and vascular smooth muscle cell deposition and increased macrophage and lymphocyte content (P<0.05 or P<0.01), which are typical features of atherosclerotic plaque instability. Additionally, the protein expression of matrix metalloproteinase (MMP)?2, MMP?9 and MMP?14 were significantly increased (P<0.05 or P<0.01), whereas tissue inhibitor of matrix metalloproteinase (TIMP)?1 expression was decreased (P<0.05) following exposure to a cold environment. The present study demonstrated that chronic intermittent cold stress may increase atherosclerotic plaque size and promote plaque instability in ApoE?deficient mice by altering the balance of MMPs and TIMPs. These findings may provide mechanistic insights into sudden cardiac death in cold environments.
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Dietary capsaicin ameliorates pressure overload-induced cardiac hypertrophy and fibrosis through the transient receptor potential vanilloid type 1.
Am. J. Hypertens.
PUBLISHED: 05-23-2014
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Dietary capsaicin plays a protective role in hypertension, atherosclerosis, obesity, and hyperlipidemia through activating the transient receptor potential vanilloid type 1 (TRPV1), a nonselective cation channel. This study was designed to investigate the role of capsaicin in cardiac hypertrophy and fibrosis in a pressure overload model.
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Activation of cold-sensing transient receptor potential melastatin subtype 8 antagonizes vasoconstriction and hypertension through attenuating RhoA/Rho kinase pathway.
Hypertension
PUBLISHED: 03-17-2014
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Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8(-/-) mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flow-mediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had favorable effects on hypertension treatment.
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Expression of mammalian target of rapamycin in atherosclerotic plaques is decreased under diabetic conditions: a mechanism for rapamycin resistance.
Mol Med Rep
PUBLISHED: 03-13-2014
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Our previous study demonstrated that diabetes increases in-stent restenosis following rapamycin-eluting stent placement, which was defined as rapamycin resistance. However, the underlying mechanisms of rapamycin resistance remain to be determined. In the present study, male apolipoprotein E-deficient (ApoE-/-) mice were randomly divided into control and diabetic groups. Diabetes was induced by injecting streptozocin (STZ). The hyperglycemic state, defined as a fasting plasma glucose level >13 mmol/l, was maintained for 8 weeks. At the end of the administration, the plasma levels of triglycerides (TG) and total cholesterol (TC) were significantly elevated in the diabetic group compared with the control mice (all P<0.01). The present study revealed that diabetes increased the atherosclerotic plaque size of the aortic root (P<0.01) and the content of vascular smooth muscle cells (VSMCs) in the atherosclerotic lesion (P<0.01). Furthermore, the protein expression and phosphorylation of mammalian target of rapamycin (mTOR), 4E-binding protein 1 and ribosomal S6 kinase 1 (P<0.01) were significantly decreased in the diabetic mice compared with the control group. The decrease in the expression and phosphorylation of mTOR and its downstream kinases may be one of the molecular mechanisms underlying rapamycin resistance.
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Transgenic Overexpression of Uncoupling Protein 2 Attenuates Salt-Induced Vascular Dysfunction by Inhibition of Oxidative Stress.
Am. J. Hypertens.
PUBLISHED: 12-04-2013
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Ablation of uncoupling protein 2 (UCP2) has been involved in the enhancement of salt sensitivity associated with increased superoxide level and decreased nitric oxide (NO) bioavailability. However, the role of overexpression of UCP2 in salt-induced vascular dysfunction remains elusive.
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Intermittent hypobaric hypoxia promotes atherosclerotic plaque instability in ApoE-deficient mice.
High Alt. Med. Biol.
PUBLISHED: 06-26-2013
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Sudden cardiac death is one of the most frequent causes of death at high altitude. It has been reported that the intermittent normobaric hypoxia experienced by patients with obstructive sleep apnea may enhance the development of atherosclerosis. However, the effect of hypobaric hypoxia, which mimics the ambient air at high altitude, in the development of atherosclerosis has not been investigated.
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Metabolic hypertension: concept and practice.
Front Med
PUBLISHED: 01-30-2013
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Hypertension is a serious public health problem worldwide. More than 60% of the risk factors for hypertension are associated with metabolic disturbances. Metabolic abnormalities increase the risk for hypertension and cause high blood pressure. Improving metabolic disturbances is beneficial for hypertension treatment. Due to the importance of metabolic abnormalities in the pathogenesis of hypertension, we propose a concept of metabolic hypertension. In this review, we discuss and review the clinical types, pathogenesis, risk evaluation and management of metabolic hypertension. Elucidation of the mechanism of metabolic hypertension should facilitate the design of novel pharmacotherapeutics and dedicated antihypertensive manipulations.
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TRPV1 activation improves exercise endurance and energy metabolism through PGC-1? upregulation in mice.
Cell Res.
PUBLISHED: 12-20-2011
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Impaired aerobic exercise capacity and skeletal muscle dysfunction are associated with cardiometabolic diseases. Acute administration of capsaicin enhances exercise endurance in rodents, but the long-term effect of dietary capsaicin is unknown. The capsaicin receptor, the transient receptor potential vanilloid 1 (TRPV1) cation channel has been detected in skeletal muscle, the role of which remains unclear. Here we report the function of TRPV1 in cultured C2C12 myocytes and the effect of TRPV1 activation by dietary capsaicin on energy metabolism and exercise endurance of skeletal muscles in mice. In vitro, capsaicin increased cytosolic free calcium and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) expression in C2C12 myotubes through activating TRPV1. In vivo, PGC-1? in skeletal muscle was upregulated by capsaicin-induced TRPV1 activation or genetic overexpression of TRPV1 in mice. TRPV1 activation increased the expression of genes involved in fatty acid oxidation and mitochondrial respiration, promoted mitochondrial biogenesis, increased oxidative fibers, enhanced exercise endurance and prevented high-fat diet-induced metabolic disorders. Importantly, these effects of capsaicin were absent in TRPV1-deficient mice. We conclude that TRPV1 activation by dietary capsaicin improves energy metabolism and exercise endurance by upregulating PGC-1? in skeletal muscles. The present results indicate a novel therapeutic strategy for managing metabolic diseases and improving exercise endurance.
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Facile synthesis of hierarchical core-shell Fe3O4@MgAl-LDH@Au as magnetically recyclable catalysts for catalytic oxidation of alcohols.
Chem. Commun. (Camb.)
PUBLISHED: 11-08-2011
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A novel core-shell structural Fe(3)O(4)@MgAl-LDH@Au nanocatalyst was simply synthesized via supporting Au nanoparticles on the MgAl-LDH surface of Fe(3)O(4)@MgAl-LDH nanospheres. The catalyst exhibited excellent activity for the oxidation of 1-phenylethanol, and can be effectively recovered by using an external magnetic field.
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Comparison of restenosis rate with sirolimus-eluting stent in STEMI patients with and without diabetes at 6-month angiographic follow-up.
Acta Cardiol
PUBLISHED: 10-29-2011
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Patients with diabetes mellitus (DM) are at high risk for restenosis after coronary stenting. However, whether drug-eluting stents are effective in diabetic patients presenting with ST-segment elevation myocardial infarction (STEMI) is uncertain. We report on a series of patients with or without DM followed up for 6 months after sirolimus-eluting stent implantation.
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Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis.
Cardiovasc. Res.
PUBLISHED: 09-09-2011
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Activation of transient receptor potential vanilloid type-1 (TRPV1) channels may affect lipid storage and the cellular inflammatory response. Now, we tested the hypothesis that activation of TRPV1 channels attenuates atherosclerosis in apolipoprotein E knockout mice (ApoE(-/-)) but not ApoE(-/-)TRPV1(-/-) double knockout mice on a high-fat diet.
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Cardiac extracellular matrix tenascin-C deposition during fibronectin degradation.
Biochem. Biophys. Res. Commun.
PUBLISHED: 04-21-2011
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Tenascin-C (TN-C) might aggravate left ventricular remodeling after myocardial infarction (MI). Our previous study demonstrated that ventricular remodeling after MI is linked with the degradation of fibronectin (FN). The aim of the present study was to determine whether cardiac extracellular matrix TN-C deposition after MI requires FN degradation. We found that treatment with angiotensin (ANG) II significantly down-regulated FN while remarkably up-regulated TN-C in co-cultured cardiomyocytes and fibroblasts. Inhibitors of matrix metalloproteinase (MMP)-2, MMP-3 or MMP-9 significantly attenuated ANG II-induced loss of FN and obviously blunted ANG II-induced re-expression of TN-C in co-cultured cells. Moreover, FN fragments dose-dependently induced the deposition of TN-C. In addition, MI induced a significant reduction of FN protein expression and a marked elevation of TN-C expression level at day 7 after MI compared with the sham group. The present findings suggest that cardiac TN-C matrix deposition after MI is induced by FN degradation, which is dependent on the activation of MMPs. These findings might contribute to gain mechanistic insights into the regulation of TN-C formation after MI.
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Oleic acid induces smooth muscle foam cell formation and enhances atherosclerotic lesion development via CD36.
Lipids Health Dis
PUBLISHED: 02-25-2011
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Elevated plasma free fatty acid (FFA) levels have been linked to the development of atherosclerosis. However, how FFA causes atherosclerosis has not been determined. Because fatty acid translocase (FAT/CD36) is responsible for the uptake of FFA, we hypothesized that the atherogenic effects of FFA may be mediated via CD36.
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BTEB2 knockdown suppresses neointimal hyperplasia in a rat artery balloon injury model.
Mol Med Rep
PUBLISHED: 02-08-2011
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Basic transcription element-binding protein 2 (BTEB2) is a regulator of the proliferation and phenotypic changes of vascular smooth muscle cells (SMCs). The aim of the present study was to determine whether or not BTEB2 knockdown inhibits balloon injury-induced neointimal hyperplasia attributed to the proliferation and phenotypic changes of vascular SMCs. We found that the knockdown of BTEB2 with antisense oligonucleotides (Ad-As-BTEB2) significantly reduced the intima/media ratio compared to uninjured arteries and vessels treated with Ad-LacZ. Knockdown of BTEB2 suppresses the proliferation of cultured vascular SMCs, concurrent with the down-regulation of proliferating cell nuclear antigen, angiotensin II type 1 receptor and platelet-derived growth factor BB. In addition, BTEB2 knockdown caused the up-regulation of the differentiation marker smooth muscle ?-actin and down-regulation of the dedifferentiation marker embryonic smooth muscle myosin heavy chain. The present study provides direct evidence that BTEB2 plays a critical role in balloon injury-induced neointimal hyperplasia, which is closely linked to vascular SMC proliferation and phenotypic modulation. This study highlights the fact that BTEB2 may be a potential target for the prevention of restenosis after vascular intervention.
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TRPV1 activation prevents high-salt diet-induced nocturnal hypertension in mice.
Pflugers Arch.
PUBLISHED: 01-19-2011
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High dietary salt-caused hypertension is associated with increasing reactive oxygen species generation and reduced nitric oxide (NO) bioavailability. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, is proposed to be involved in Dahl salt-sensitive hypertension, as determined in acute or short-term experiments. However, it remains unknown whether activation of TRPV1 by dietary capsaicin could prevent the vascular oxidative stress and hypertension induced by a high-salt diet. Here, we report that consumption of a high-salt diet blunted endothelium-dependent relaxation in mesenteric resistance arteries and elevated nocturnal blood pressure in mice. These effects were associated with increased superoxide anion generation and reduced NO levels in mesenteric vessels in mice on a high-salt diet. However, chronic administration of capsaicin reduced the high-salt diet-induced endothelial dysfunction and nocturnal hypertension in part by preventing the generation of superoxide anions and NO reduction of mesenteric arteries through vascular TRPV1 activation. Our findings provide new insights into the role of TRPV1 channels in the long-term regulation of blood pressure in response to high-salt intake. TRPV1 activation through chronic dietary capsaicin may represent a promising lifestyle intervention in populations with salt-sensitive hypertension.
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Overexpression of angiotensin II type 2 receptor suppresses neointimal hyperplasia in a rat carotid arterial balloon injury model.
Mol Med Rep
PUBLISHED: 01-14-2011
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Angiotensin II (ANG II) type 2 receptor (AT2R) has been recognized to suppress the proliferation of vascular smooth muscle cells (VSMCs). The aim of the present study was to determine whether AT2R overexpression inhibits neointimal hyperplasia in a rat carotid arterial balloon injury model and to examine the underlying mechanisms of its activity. Balloon-injured rats receiving Ad-AT2R showed significant diminutions in neointimal area and intima/media ratio compared to non-treated rats or rats receiving adenovirus containing green fluorescent protein (Ad-GFP). In addition, extracellular regulated kinase 1/2 (ERK1/2) and basic transcription element-binding protein 2 (BTEB2) were significantly down-regulated in the arteries and VSMCs of Ad-AT2R-treated rats and compared to Ad-GFP-treated rats. However, Ad-AT2R transfection failed to affect the expression of ANG II type 1 receptor (AT1R) in carotid arteries and cultured VSMCs. The present study provides direct evidence that AT2R plays a beneficial role in balloon injury-induced neointimal hyperplasia, which is mainly attributed to the inhibition of VSMC proliferation and involves the down-regulation of the ERK1/2 and BTEB2 pathways, but is independent of the expression of AT1R.
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TRP channels and their implications in metabolic diseases.
Pflugers Arch.
PUBLISHED: 08-26-2010
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The transient receptor potential (TRP) channel superfamily is composed of 28 nonselective cation channels that are ubiquitously expressed in many cell types and have considerable functional diversity. Although changes in TRP channel expression and function have been reported in cardiovascular disease and renal disorders, the pathogenic roles of TRP channels in metabolic diseases have not been systemically reviewed. In this review, we summarised the distribution of TRP channels in several metabolic tissues and discussed their roles in mediating and regulating various physiological and pathophysiological metabolic processes and diseases including diabetes, obesity, dyslipidaemia, metabolic syndrome, atherosclerosis, metabolic bone diseases and electrolyte disturbances. This review provides new insight into the involvement of TRP channels in the pathogenesis of metabolic disorders and implicates these channels as potential therapeutic targets for the management of metabolic diseases.
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Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure.
Int. J. Mol. Med.
PUBLISHED: 06-02-2010
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The angiotensin (Ang) II/Ang II receptor (ATR)-associated calcium signaling pathway is the major cause of ventricular remodelling in patients with congestive heart failure (CHF). However, the calcium-regulated proteinases responsible for Ang II-induced remodelling are not well understood. We investigated the profiles of the Ang II/ATR/calpain/calcineurin (CaN) pathway in human failing heart. We measured both the plasma and cardiac levels of Ang II and cardiac mRNA expression of ATR in 39 patients with CHF and 38 healthy controls. Importantly, protein expression of calpains, cleavage of cain/cabin1 and activity of CaN were tested. Both plasma and cardiac levels of Ang II were significantly increased in patients with CHF (both p<0.01), and the plasma Ang II concentration was closely correlated with the parameters of ventricular remodelling (r=+/-0.29-0.65, p<0.05 or <0.01). In addition, the cardiac level of AT1R but not AT2R was significantly upregulated in mild failing hearts (p<0.05) but dramatically downregulated in severe failing ones (p<0.01). CHF was associated with a marked upregulation of calpains, an increased cleavage of cain/cabin1, and the activation of CaN in the failing ventricular tissue. In patients with CHF, calpain upregulation was associated with an increase in cleavage of cain/cabin1 and the activation of CaN, indicating that these changes in calcium-regulated proteinases contribute to Ang II-induced cardiac remodelling.
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Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension.
Cell Metab.
PUBLISHED: 05-17-2010
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Some plant-based diets lower the cardiometabolic risks and prevalence of hypertension. New evidence implies a role for the transient receptor potential vanilloid 1 (TRPV1) cation channel in the pathogenesis of cardiometabolic diseases. Little is known about impact of chronic TRPV1 activation on the regulation of vascular function and blood pressure. Here we report that chronic TRPV1 activation by dietary capsaicin increases the phosphorylation of protein kinase A (PKA) and eNOS and thus production of nitric oxide (NO) in endothelial cells, which is calcium dependent. TRPV1 activation by capsaicin enhances endothelium-dependent relaxation in wild-type mice, an effect absent in TRPV1-deficient mice. Long-term stimulation of TRPV1 can activate PKA, which contributes to increased eNOS phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats. We conclude that TRPV1 activation by dietary capsaicin improves endothelial function. TRPV1-mediated increase in NO production may represent a promising target for therapeutic intervention of hypertension.
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Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-?/AMPK pathway.
J. Cell. Mol. Med.
PUBLISHED: 05-14-2010
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Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor ? (PPAR-?) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-?-deficient mice. Administration of telmisartan up-regulated levels of PPAR-? and phospho-AMPK? in cultured myotubes. However, PPAR-? gene deficiency completely abolished the telmisartan effect on phospho-AMPK?in vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-?-deficient mice. The mechanism is involved in PPAR-?-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPK? level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPK? expression in skeletal muscle was unchanged in PPAR-?-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-? as a potential therapeutic target for the prevention of type 2 diabetes.
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Uncoupling protein 2 ablation exacerbates high-salt intake-induced vascular dysfunction.
Am. J. Hypertens.
PUBLISHED: 04-15-2010
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Salt-induced vascular dysfunction in which underlying mechanisms involve reactive oxygen species (ROS)-mediated reduction of nitric oxide (NO) bioavailability has been well documented. Uncoupling protein 2 (UCP2) has been implicated in the vascular protection, specifically by decreasing ROS production. However, it is unclear how UCP2 affects vascular function in salt-loaded mice.
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Adrenergic receptor blockade-induced regression of pressure-overload cardiac hypertrophy is associated with inhibition of the calcineurin/NFAT3/GATA4 pathway.
Mol Med Rep
PUBLISHED: 03-09-2010
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Calcineurin and its downstream effectors nuclear factor of activated T-cells 3 (NFAT3) and zinc finger-containing transcription factor (GATA4) have been implicated in the development of cardiac hypertrophy. The aims of the present study were to investigate alterations in the calcineurin/NFAT3/GATA4 pathway in pressure-overload hypertrophy, and to determine whether adrenergic receptor blockade affects this signaling pathway. In aorta-banded rats compared with sham-operated rats, a significant increase in the phosphorylation levels of calcineurin and GATA4 was observed (both p<0.05), while the NFAT3 phosphorylation level was markedly decreased (p<0.05). Oral administration of either the non-selective ? blocker/?-1 blocker carvedilol or the selective ?-1 blocker metoprolol, but not the selective ?-1 blocker terazosin, significantly suppressed the activated calcineurin/NFAT3/GATA4 pathway (all p<0.05) in addition to inducing a regression of cardiac hypertrophy. Pressure overload-induced up-regulation of c-myc was markedly attenuated by treatment with either carvedilol or metoprolol (both p<0.05). The present findings may expand our understanding of the correlation between sympathetic activity and the calcineurin/NFAT3/GATA4 pathway, and highlight these signal transducers as effective targets in the management of pressure overload-induced cardiac hypertrophy.
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Perivascular fat-mediated vascular dysfunction and remodeling through the AMPK/mTOR pathway in high-fat diet-induced obese rats.
Hypertens. Res.
PUBLISHED: 02-26-2010
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Perivascular adipose tissue (PVAT) is implicated in the regulation of vascular function in the physiological state, but the modulatory effect of PVAT on vasculature during obesity is poorly understood. Endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) participate in the regulation of vascular function. We therefore investigated whether PVAT has a potential role through the AMPK/mTOR pathway in obesity-related vascular dysfunction. Wistar rats on a high-fat diet (HFD) for 6 months had higher periaortic fat mass compared with rats on a chow diet (3.31+/-0.56 vs. 2.34+/-0.28 g, P<0.05). Obesity-related impairment of endothelium-dependent relaxation of the aorta was markedly attenuated by temporary periaortic fat removal whereas obesity-related enhancement of contractile performance was unaffected. Rats on an HFD had thicker aortic tunica medias (180.06+/-7.56 vs. 128.14+/-13.21 microm for rats on a chow diet, P<0.01) and larger periaortic adipocytes than rats on a chow diet (1209.00+/-62.65 vs. 447.20+/-21.31 microm(2), respectively, P<0.01). Furthermore, mesenteric arterial rings incubated with periaortic fat from rats on an HFD demonstrated lower endothelium-dependent relaxation. This effect was absent in mesenteric arterial rings incubated with periaortic fat from rats on a chow diet. Moreover, an HFD led to a downregulation of AMPK and eNOS in the aorta with a concurrent upregulation of mTOR. In a parallel in vitro study, culturing vascular smooth muscle cells with periaortic adipocytes from rats on an HFD reduced the AMPK phosphorylation and increased mTOR phosphorylation, and the latter one was blocked by the incubation of compound C. We conclude that PVAT likely impacts obesity-related vascular dysfunction and remodeling through impairment of eNOS-mediated vasodilatation and the AMPK/mTOR pathway.
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Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways.
Hypertension
PUBLISHED: 02-22-2010
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Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-delta-dependent pathways in several tissues. In vitro, telmisartan significantly upregulated PPAR-delta expression in 3T3-L1 preadipocytes in a time- and dose-dependent manner. Other than enhancing PPAR-delta expression by 68.2+/-17.3% and PPAR-delta activity by 102.0+/-9.0%, telmisartan also upregulated PPAR-gamma expression, whereas neither candesartan nor losartan affected PPAR-delta expression. In vivo, long-term administration of telmisartan significantly reduced visceral fat and prevented high-fat diet-induced obesity in wild-type mice and hypertensive rats but not in PPAR-delta knockout mice. Administration of telmisartan did not influence food intake in mice. Telmisartan influenced several lipolytic and energy uncoupling related proteins (UCPs) and enhanced phosphorylated protein kinase A and hormone sensitive lipase but reduced perilipin expression and finally inhibited adipogenesis in 3T3-L1 preadipocytes. Telmisartan-associated reduction of adipogenesis in preadipocytes was significantly blocked after PPAR-delta gene knockout. Chronic telmisartan treatment upregulated the expressions of protein kinase A, hormone-sensitive lipase, and uncoupling protein 1 but reduced perilipin expression in adipose tissue and increased uncoupling protein 2 and 3 expression in skeletal muscle in wild-type mice but not in PPAR-delta knockout mice. We conclude that telmisartan prevents adipogenesis and weight gain through activation of PPAR-delta-dependent lipolytic pathways and energy uncoupling in several tissues.
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Angiotensin II receptor blockade improves matrix metalloproteinases/tissue inhibitor of matrix metalloproteinase-1 balance and restores fibronectin expression in rat infarcted myocardium.
Biochem. Biophys. Res. Commun.
PUBLISHED: 08-05-2009
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Matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) have been recognized to play a pivotal role in matrix remodeling following myocardial infarction (MI). The aims of the present study were to examine the expression profile of MMPs/TIMP-1 after MI and to determine whether angiotensin II receptor (ATR) blockade improves MMPs/TIMP-1 balance. Compared with sham-operated rats, in vivo MI-induced a significant elevation of MMP-2, MMP-3 and MMP-9 levels and a marked reduction of TIMP-1 and fibronectin (FN) expressions in infarcted left ventricular free wall (LVFW) and hypertrophic interventricular septum (IS) but not in non-infarcted right ventricle (RV). In addition, regional MI increased MMP-2, MMP-3 and MMP-9, while decreased TIMP-1 and FN in infarcted LVFW and hypertrophic IS compared with the non-infarcted RV. Compared with vehicle-treated MI rats, oral valsartan, but not PD123319, limited infarct size, normalized MMPs/TIMP-1 balance and restored FN level. The present findings might further our understanding of the regulatory mechanisms of valsartan in myocardial remodeling after MI.
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Establishment of a conditional transgenic mouse model expressing human uncoupling protein 2 in vascular smooth muscle cells.
Exp Ther Med
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Increased oxidative stress is involved in the development of vascular dysfunction and remodeling. Uncoupling protein 2 (UCP2) regulates the production of reactive oxygen species in vascular smooth muscle cells (SMCs). To promote the study of the role of UCP2 in vascular diseases, a transgenic mouse model expressing human UCP2 (hUCP2) in vascular SMCs was established. We constructed a plasmid carrying the 2.3 kb rabbit smooth muscle myosin heavy chain promoter and the hUCP2 gene. We used this plasmid to produce transgenic mice by pro-nuclear microinjection. Six offspring were identified as founder mice that were used to establish a transgenic mouse lineage. The transgenic mice showed a significant increase in hUCP mRNA expression in the aorta. Moreover, hUCP2 overexpression inhibited the production of superoxide and increased the bioavailability of nitric oxide (NO). In this study, we established a hUCP2 transgenic mouse model, which will enable further studies on the role of UCP2 in vascular dysfunction and remodeling.
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Inhibition of uncoupling protein 2 with genipin exacerbates palmitate-induced hepatic steatosis.
Lipids Health Dis
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Uncoupling protein 2 (UCP2) was reported to be involved in lipid metabolism through regulating the production of superoxide anion. However, the role of UCP2 in hepatocytes steatosis has not been determined. We hypothesized that UCP2 might regulate hepatic steatosis via suppressing oxidative stress.
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Acipimox attenuates atherosclerosis and enhances plaque stability in ApoE-deficient mice fed a palmitate-rich diet.
Biochem. Biophys. Res. Commun.
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Saturated fatty acids (FA) have been linked to an increased risk of cardiovascular disease. The effects of acipimox, a FA-lowering agent, on palmitate- (an important saturated fatty acid) stimulated atherosclerosis remains to be elucidated. We investigated the effects of acipimox on atherosclerosis in ApoE(-/-) mice fed a palmitate-rich diet. Male ApoE(-/-) mice, 6-8 weeks of age, were randomized into three groups. The animals were fed a normal chow diet in the control group, a diet containing 5% palmitic acid in the palmitate group, and a diet containing 5% palmitic acid and 0.02% acipimox in the acipimox group. The plasma lipid profiles, aortic lesions, plaque collagen content and the expression of matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, and MMP-14 and the tissue inhibitor of MMP (TIMP)-1, and TIMP-2 were determined after a 12-week treatment. The palmitate-rich diet significantly increased plasma FA concentrations (P<0.01), enhanced atherosclerotic lesions (P<0.01), decreased plaque collagen content (P<0.01) and upregulated MMP-2 (P<0.05) in the aorta. Additionally, all of these harmful effects were significantly attenuated by co-treatment with acipimox (P<0.05 or P<0.01). The present study suggests that acipimox attenuates atherosclerosis and enhances plaque stability in ApoE(-/-) mice fed a palmitate-rich diet.
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Cryptotanshinone attenuates isoprenaline-induced cardiac fibrosis in mice associated with upregulation and activation of matrix metalloproteinase-2.
Mol Med Rep
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Cryptotanshinone is an active ingredient of Salvia miltiorrhiza that has been used in traditional Chinese medicine for treating cardiovascular disorders. Thus, we investigated the effects of cryptotanshinone on cardiac fibrosis induced by isoprenaline and examined whether cardiac matrix metalloproteinase (MMP)-2 is involved in this process. Male C57BL/6 mice received a daily injection of 0.9% saline, 3 mg/kg isoprenaline or isoprenaline plus 20 mg/kg cryptotanshinone by gastric gavage for 2 weeks. In this study we demonstrated that cryptotanshinone was able to significantly ameliorate isoprenaline-induced cardiac fibrosis, which was associated with a marked upregulation and activation of MMP-2 in the ventricular myocardium. Additionally, we demonstrated that cryptotanshinone dose-dependently upregulated and activated MMP-2 in cultured cardiac fibroblasts. Moreover, incubation with cryptotanshinone also prevented the isoprenaline-induced downregulation and inactivation of MMP-2 in cultured cardiac fibroblasts. Taken together, our data suggest that cryptotanshinone is a novel and potent antifibrotic agent. The present findings further our understanding of the role of MMP-2 in cardiac fibrosis and the antifibrotic mechanisms of cryptotanshinone.
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Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity.
J Mol Cell Biol
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Brown adipose tissue (BAT) is an energy-expending organ that produces heat. Expansion or activation of BAT prevents obesity and diabetes. Chronic cold exposure enhances thermogenesis in BAT through uncoupling protein 1 (UCP1) activation triggered via a ?-adrenergic pathway. Here, we report that the cold-sensing transient receptor potential melastatin 8 (TRPM8) is functionally present in mouse BAT. Challenging brown adipocytes with menthol, a TRPM8 agonist, up-regulates UCP1 expression and requires protein kinase A activation. Upon mimicking long-term cold exposure with chronic dietary menthol application, menthol significantly increased the core temperatures and locomotor activity in wild-type mice; these effects were absent in both TRPM8(-/-) and UCP1(-/-) mice. Dietary obesity and glucose abnormalities were also prevented by menthol treatment. Our results reveal a previously unrecognized role for TRPM8, suggesting that stimulation of this channel mediates BAT thermogenesis, which could constitute a promising way to treat obesity.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.