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Li L.,Peking University | Zhang Z.-G.,Peking University | Lei H.,Peking University | Wang C.,Peking University | And 5 more authors.
PLoS ONE | Year: 2013

Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII. © 2013 Li et al.


Chen S.,Peking University | Chen S.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Chen S.,Key Laboratory of Molecular Cardiovascular science | Guo L.,Peking University | And 11 more authors.
Experimental and Therapeutic Medicine | Year: 2013

The aim of the present study was to investigate the association of the serum angiopoietin (Ang)-1 and Ang-2 levels and the Ang-2 to Ang-1 ratio (Ang-2/Ang-1) with heart failure (HF) in patients with acute myocardial infarction (AMI) during hospitalization. The serum Ang-1 and Ang-2 levels of the AMI patients were measured at admission to hospital. The correlations between serum Ang-1, Ang-2 and Ang-2/Ang-1 with HF were examined. Among 103 patients, 20 developed HF during hospitalization. The serum Ang-2 level and Ang-2/Ang-1 were found to be significantly higher in the patients with HF than in the patients without HF (2,203.1±122.0 vs. 2,102.3±114.4 pg/ml, P=0.001 and 11.4±1.6x10-2 vs. 10.6±1.1x10-2, P=0.007, respectively). Serum Ang-2 level and Ang-2/Ang-1 were negatively correlated with left ventricular ejection fraction (LVEF; r=-0.352, P<0.001 and r=0.365, P<0.001, respectively) and positively correlated with the natural logarithm of the level of N-terminal pro-B-type natriuretic peptide (LnNT-proBNP, r=0.367, P<0.001 and r=0.304, P=0.003, respectively) and peak cardiac troponin T (cTnT, r=0.421, P<0.001 and r=0.278, P=0.009, respectively). However, the serum Ang-1 level was not found to correlate significantly with LVEF (r=0.194, P=0.05), LnNT-proBNP (r=-0.116, P=0.266) or peak cTnT (r=0.056, P=0.607). In multivariable logistic regression analysis, Ang-2 (P=0.031), Ang-2/Ang-1 (P=0.018) and NT-proBNP (P=0.001) were revealed to be independently associated with HF. The present study reveals that Ang-2 levels and Ang-2/Ang-1 are independent predictors of HF in AMI patients during hospitalization.


Yu J.,Peking University | Yu J.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Han J.L.,Peking University | Han J.L.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | And 6 more authors.
Chinese Medical Journal | Year: 2014

Background Many studies have shown that the serum uric acid (SUA) level is one of the cardiovascular risk factors. The aim of the study is to evaluate the relationship between SUA levels and the severity of coronary artery disease (CAD) assessed by angiography and the Syntax score in patients with obstructive CAD. Methods Participants who visited our hospital for a coronary angiography, from December 2007 to September 2012, were eligible for this analysis. SUA and other blood parameters after at least 12-hour fast were determined. First, the patients were divided into tertiles according to their Syntax scores (low Syntax score group: Syntax score ≤10.0; moderate Syntax score group: 10.0 18.0). Second, to clarify the association between SUA levels and major adverse cardiovascular events (MACEs), all patients were divided into two subgroups on the basis of SUA levels. The cutoff value of SUA was defined by diagnostic criteria of hyperuricemia. Patients were separated into normal SUA group (n=251, with SUA <416 μmol/L for men and SUA <357 μmol/L for women) and high SUA group (n=96, with SUA ≥416 μmol/L for men and SUA ≥357 μmol/L for women). All participants were followed for a mean of 22.0 months (1-75 months, interquartile range: 28 months) for major adverse cardiovascular events (MACEs), including all-cause death, recurrent nonfatal myocardial infarction (re-MI) and recurrent percutaneous coronary intervention (re-PCI). Results A total of 347 patients were registered for the study. The SUA levels in the high Syntax score group were significantly higher than that of the moderate Syntax score group and the low Syntax score group ((392.3±81.6) μmol/L vs. (329.9±71.0) μmol/L, P <0.001; (392.3±81.6) μmol/L vs. (311.4±64.7) μmol/L, P <0.001). The SUA level was positively correlated not only with the Syntax score (r=0.421, P <0.001; 95% CI: 0.333-0.512), but also with the number of diseased vessels (r=0.298, P <0.001; 95% CI: 0.194-0.396). After multiple linear regression analysis, SUA levels were identified to be independently correlated with a high Syntax score (B=0.033, 95% CI 0.023-0.042, P <0.001). Compared with the normal SUA subgroup, the high SUA subgroup tended to have a higher Syntax score (19.9±8.7 vs. 13.6±7.5, P <0.001) and more multi-vessel disease (70.8% vs. 46.6%, P <0.001). Follow-up data showed a higher incidence of MACE in the high SUA subgroup (20.8% vs. 6.0%, P <0.001). Binary Logistic regression analysis indicated that the elevated SUA can predict the long-term prognosis of patients with obstructive CAD (OR=2.968, 95% CI 1.256-7.011, P=0.013). Kaplan-Meier analysis showed a significantly lower event-free survival rate in patients with high SUA levels than in the normal SUA subgroup (79.2% vs. 94.0%, Log rank=17.645, P <0.001). Conclusions SUA levels were independently associated with the severity of CAD in patients with obstructive CAD. An elevated SUA is associated with cardiovascular events and may be useful as a biomarker of the severity of CAD.


Li L.,Peking University | Li L.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Li H.-Y.,Peking University | Li H.-Y.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | And 8 more authors.
Chinese Medical Journal | Year: 2013

Background Despite outstanding antiplatelet properties of aspirin and clopidogrel, some patients taking these drugs continue to suffer complications. Antiplatelet resistance appears to be a new prognostic factor in acute coronary syndrome patients for clinical events associated with stent thrombosis (ST). However, there is no optimal method to identify it and assess its correlation to clinical outcomes. This study sought to evaluate the predictive value of antiplatelet resistance assessed by whole blood impedance aggregometry for the risk of early ST in patients with acute coronary syndrome who underwent coronary stenting. Methods Platelet responses to aspirin and clopidogrel in 86 patients with acute coronary syndrome were measured by whole blood impedance aggregometry. Spontaneous platelet aggregation was defined as antiplatelet resistance identified by the increased electrical impedance. The clinical endpoint was early stent thrombosis during 30-day follow-up after coronary stenting. Results The prevalence of aspirin resistance, clopidogrel resistance and dual resistance of combined clopidogrel and aspirin resistance were 19.8%, 12.8% and 5.8% respectively. Diabetes, female and higher platelet counts were more frequently detected in clopidogrel-resistant and dual-resistant patients. During 30-day follow-up, the patients with clopidogrel resistance and dual resistance had higher incidence of early stent thrombosis (18.2% vs. 1.3%, 40.0% vs. 1.2%, P <0.05). Binary Logistic Regression analysis indicated that dual resistance remained an independent predicator for early stent thrombosis (odds ratio 34.064, 95% CI 1.919-604.656, P=0.016). Conclusions Antiplatelet resistance assessed by whole blood impedance aggregometry is paralleled to clinical events, and dual antiplatelet resistance is an independent predicator for early stent thrombosis in patients with acute coronary syndrome. As a physiological assessment of platelet reactivity, whole blood impedance aggregometry is a convenient and accurate option for measuring antiplatelet resistance and hence predicting early stent thrombosis.


Zuo B.,Peking University | Zuo B.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory peptides | Wang F.,Peking University | Wang F.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory peptides | And 6 more authors.
Current Medical Research and Opinion | Year: 2015

Background and aims: It remains uncertain whether remote ischemic conditioning (RIC) could prevent acute kidney injury (AKI) in patients undergoing percutaneous coronary intervention (PCI). Thus, this meta-analysis aiming to explore the renoprotective role of RIC in patients undergoing PCI was carried out. Methods: PubMed, Web of Science, and Cochrane Library were searched from inception to 31 December 2014 to identify eligible randomized controlled trials. Pooled risk ratio, mean, standard deviation and 95% CI were used to assess the effect by fixed- or random-effect models. Heterogeneity was assessed by the Cochran Q and I 2 statistics. Results: Nine trials were included in this study. RIC decreased the AKI incidence in patients undergoing PCI compared with control individuals (P<0.001; RR, 0.53; 95% CI, 0.39-0.71; P for heterogeneity=0.15; heterogeneity X2=13.38; I2=33%). Besides, limb conditioning attenuated AKI (P=0.001; RR, 0.57; 95% CI, 0.41-0.81; P for heterogeneity=0.13; heterogeneity X2=12.48; I2=36%). Remote postconditioning may reduce the AKI incidence (P=0.03; RR, 0.65; 95% CI, 0.44-0.97; P for heterogeneity=0.15; heterogeneity X2=5.36; I2=44%); remote preconditioning could also play a renoprotective role (P<0.001; RR, 0.42; 95% CI, 0.27-0.65; P for heterogeneity=0.31; heterogeneity X2=5.98; I2=16%). Conclusions: RIC may not only confer cardioprotection, but also reduce the incidence of AKI in patients undergoing PCI, ultimately leading to better clinical outcomes. RIC may potentially be a powerful approach conferring protection in patients undergoing PCI in future clinical practice. More large-scale trials are required to obtain a more reliable conclusion. © 2015 Informa UK Ltd.


Yan L.-Q.,Peking University | Yan L.-Q.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Yan L.-Q.,Hebei Medical University | Guo L.-J.,Peking University | And 5 more authors.
Canadian Journal of Cardiology | Year: 2011

Background: Chronic kidney disease (CKD) is highly prevalent in patients with coronary artery disease (CAD) and is an independent risk factor for adverse cardiovascular disease (CVD) and all-cause mortality in patients with acute coronary syndromes. SYNTAX score (SXscore) can predict the outcomes of patients undergoing percutaneous coronary intervention. However, the association between kidney function and SXscore has not been previously reported. Methods: The estimated glomerular filtration rate (eGFR) and SXscore were retrospectively collected in 2262 patients with established CAD undergoing coronary angiography at Peking University Third Hospital from March 2005 to September 2010. Ordinal logistic regression and Pearson and partial correlation were used to analyze the association between eGFR and SXscore. Results: Patients with renal dysfunction were older, more likely to be female, and have a history of hypertension and diabetes. The unadjusted correlation coefficient of eGFR and SXscore was -0.125 (P < 0.001).This remained significant after adjustment for age, sex, hypertension, diabetes, hyperlipidemia, or current smoking (r = -0.075, P = 0.019). Ordinal logistic regression showed that age, gender, diabetes, and eGFR exerted independent influences on SXscore. Conclusions: Kidney function was an independent predictor of SXscore in patients with established CAD. This helps explain the increased risk of cardiovascular disease events and mortality in patients with renal dysfunction. Further prospective multicentre studies are needed to confirm this finding. © 2011 Canadian Cardiovascular Society.


Zhou Y.,Peking University | Zhou Y.,Key Laboratory of Molecular Cardiovascular science | Zhou Y.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Wang J.-Y.,Peking University | And 21 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

Objective - Vascular calcification is highly correlated with increased cardiovascular morbidity and mortality. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine that plays important roles in cardiovascular system. Here, we investigated the role of CTRP3 in vascular calcification and its underlying mechanism. Approach and Results - Adenine-induced chronic renal failure rat model was used to mimic the process of arterial medial calcification. The level of CTRP3 was elevated in serum and abdominal aorta of chronic renal failure rats. Periadventitial gene delivery of CTRP3 significantly accelerated the calcification of abdominal aorta and arterial ring. In cultured vascular smooth muscle cells (VSMCs), CTRP3 increased β-glycerophosphate-induced calcium deposition and alkaline phosphatase activity. Although CTRP3 alone was not sufficient to induce calcification in VSMCs, it upregulated the expression of osteogenic marker genes including runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2, and osteopontin. CTRP3 further enhanced β-glycerophosphate-induced downregulation of smooth muscle α-actin and smooth muscle 22α, while augmenting osteogenic marker expression in VSMCs induced by β-glycerophosphate. In contrast, knockdown of CTRP3 in VSMCs potently suppressed β-glycerophosphate-induced calcification. Mechanistically, knockdown of Runx2 inhibited CTRP3-promoted VSMC calcification. CTRP3 increased extracellular signal-regulated kinase 1/2 phosphorylation and reactive oxygen species production. Preincubation with U0126, an extracellular signal-regulated kinase 1/2 upstream kinase inhibitor, had no effect on CTRP3-induced reactive oxygen species production. However, pretreatment with N-acetyl-L-cysteine, a reactive oxygen species scavenger, suppressed CTRP3-induced extracellular signal-regulated kinase 1/2 phosphorylation. Both N-acetyl-L-cysteine and U0126 significantly inhibited CTRP3-induced upregulation of Runx2 and calcified nodule formation. Conclusions - CTRP3 promotes vascular calcification by enhancing phosphate-induced osteogenic transition of VSMC through reactive oxygen species-extracellular signal-regulated kinase 1/2-Runx2 pathway. © 2014 American Heart Association, Inc.


Wang C.,Peking University | Wen J.,China Japan Friendship Hospital | Zhou Y.,Peking University | Li L.,Peking University | And 6 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2015

Apelin is an adipokine that has a critical role in the development of atherosclerosis, which may offer potential for therapy. Because migration of vascular smooth muscle cells (VSMCs) is a key event in the development of atherosclerosis, understanding its effect on the atherosclerotic vasculature is needed. Here we investigated the effect of apelin on VSMC migration and the possible signaling mechanism. In cultured rat VSMCs, apelin dose- and time-dependently promoted VSMC migration. Apelin increased the phosphorylation of Akt, whereas LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), and an Akt1/2 kinase inhibitor blocked the apelin-induced VSMC migration. Apelin dose-dependently induced phosphorylation of Forkhead box O3a (FoxO3a) and promoted its translocation from the nucleus to cytoplasm, which were blocked by LY294002 and Akt1/2 kinase inhibitor. Furthermore, apelin increased matrix metalloproteinase 2 (MMP-2) expression and gelatinolytic activity. Overexpression of a constitutively active, phosphorylation-resistant mutant, TM-FoxO3a, in VSMCs abrogated the effect of apelin on MMP-2 expression and VSMC migration. ARP101, an inhibitor of MMP-2, suppressed apelin-induced VSMC migration. Moreover, the levels of apelin, phosphorylated Akt, FoxO3a, and MMP-2 were higher in human carotid-artery atherosclerotic plaque than in adjacent normal vessels. We demonstrate that PI3K/Akt/FoxO3a signaling may be involved in apelin inducing VSMC migration. Phosphorylation of FoxO3a plays a central role in mediating the apelin-induced MMP-2 activation and VSMC migration. © 2015 Published by Elsevier Ltd.


PubMed | Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Chinese Institute of Clinical Medical Sciences, Peking University and China Japan Friendship Hospital
Type: | Journal: The international journal of biochemistry & cell biology | Year: 2015

Apelin is an adipokine that has a critical role in the development of atherosclerosis, which may offer potential for therapy. Because migration of vascular smooth muscle cells (VSMCs) is a key event in the development of atherosclerosis, understanding its effect on the atherosclerotic vasculature is needed. Here we investigated the effect of apelin on VSMC migration and the possible signaling mechanism. In cultured rat VSMCs, apelin dose- and time-dependently promoted VSMC migration. Apelin increased the phosphorylation of Akt, whereas LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), and an Akt1/2 kinase inhibitor blocked the apelin-induced VSMC migration. Apelin dose-dependently induced phosphorylation of Forkhead box O3a (FoxO3a) and promoted its translocation from the nucleus to cytoplasm, which were blocked by LY294002 and Akt1/2 kinase inhibitor. Furthermore, apelin increased matrix metalloproteinase 2 (MMP-2) expression and gelatinolytic activity. Overexpression of a constitutively active, phosphorylation-resistant mutant, TM-FoxO3a, in VSMCs abrogated the effect of apelin on MMP-2 expression and VSMC migration. ARP101, an inhibitor of MMP-2, suppressed apelin-induced VSMC migration. Moreover, the levels of apelin, phosphorylated Akt, FoxO3a, and MMP-2 were higher in human carotid-artery atherosclerotic plaque than in adjacent normal vessels. We demonstrate that PI3K/Akt/FoxO3a signaling may be involved in apelin inducing VSMC migration. Phosphorylation of FoxO3a plays a central role in mediating the apelin-induced MMP-2 activation and VSMC migration.


Wang J.,Beijing Institute of Biotechnology | Song Y.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Zhang Y.,Beijing Institute of Biotechnology | Xiao H.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | And 13 more authors.
Cell Research | Year: 2012

Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases. © 2012 IBCB, SIBS, CAS All rights reserved.

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