Beijing Key Laboratory of Cardiovascular Receptors Research

Beijing, China

Beijing Key Laboratory of Cardiovascular Receptors Research

Beijing, China
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Zhang C.-L.,Peking University | Zhang C.-L.,Key Laboratory of Molecular Cardiovascular Science | Zhang C.-L.,Beijing Key Laboratory of Cardiovascular Receptors Research | Feng H.,Peking University | And 19 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2017

Background Mitochondrial biogenesis is crucial for the maintenance of mitochondrial function and cellular homeostasis. C1q/tumor necrosis factor-related protein-3 (CTRP3) is an adipokine that owns multiple functions on metabolic and cardiovascular diseases. However, whether CTRP3 affects mitochondrial biogenesis in cardiomyocytes remains unknown. Methods Neonatal rat ventricular myocytes were cultured and treated with globular CTRP3 (gCTRP3). The expression of mitochondrial biogenesis related genes was measured by real-time PCR and western blot analysis. Mitochondrial morphology was assessed by a transmission electron microscope. ATP content, oxygen consumption rate (OCR), and sirtuin1 activity were measured with commercial kits. Results gCTRP3 increased the expression of peroxisome proliferators activated receptor-γ co-activator-1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), NRF-2, mitochondrial transcription factor A (TFAM), cytochrome B, and oxidative phosphorylation complexes III and V, and increased mitochondrial cristae components and OCR. Additionally, gCTRP3 enhanced mitochondrial DNA copy number and ATP content, while the induction was inhibited by knockdown of PGC-1α via small interfering RNA. gCTRP3 increased phosphorylation of AMP-activated protein kinase (AMPK), whereas adenine 9-β-D-arabinofuranoside (AraA), an AMPK inhibitor, attenuated gCTRP3-mediated induction of NRF-1, TFAM, and complexes III and V. gCTRP3 increased both the expression and activity of sirtuin1, whereas inhibition of sirtuin1 by EX-527 attenuated gCTRP3-induced responses. Meanwhile, gCTRP3-mediated activation of sirtuin1 was attenuated by AraA. Moreover, gCTRP3 restored the reduction of sirtuin1, PGC-1α, NRF-1, complex III and ATP content induced by hypoxia-reoxygenation injury. Conclusion CTRP3 promotes mitochondrial biogenesis in cardiomyocytes via AMPK/PGC-1α pathway. General significance CTRP3 is an endogenous modulator for mitochondrial biogenesis, and may protect cardiomyocytes by ameliorating mitochondrial dysfunction. © 2016 Elsevier B.V.

Feng Y.,Peking University | Feng Y.,Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides | Feng Y.,Key Laboratory of Molecular Cardiovascular science | Feng Y.,Beijing Key Laboratory of Cardiovascular Receptors Research | And 12 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2017

Metformin is a well-known AMP-activated protein kinase (AMPK) activator, and it has been shown to inhibit organ fibrosis. Whether AMPKα2 mediates metformin protection against renal fibrosis remains unknown. Here, we aimed to investigate the role of the AMPKα2 isoform in mediating the inhibitory effect of metformin on renal fibrosis. Unilateral ureteral obstruction (UUO) was used to induce renal fibrosis in wild-type (WT) and AMPKα2 knockout (AMPKα2−/−) mice. Metformin treatment was initiated 3 days before UUO and was continued until 7 days after UUO. In WT mice, metformin significantly inhibited UUO-induced renal fibrosis. In AMPKα2−/− mice, metformin also tended to inhibit UUO-induced renal fibrosis. Specifically, metformin significantly reduced UUO-induced transforming growth factor β1 (TGFβ1) mRNA and protein expression in WT mice but not in AMPKα2−/− mice. In contrast, metformin reduced UUO-induced TGFβ1 downstream Smad3 phosphorylation in both WT and AMPKα2−/− mice, suggesting that this regulation occurs in an AMPKα2-independent manner. In conclusion, the underlying mechanisms for the protective effects of metformin against renal fibrosis include AMPKα2-dependent targeting of TGFβ1 production and AMPKα2-independent targeting of TGFβ1 downstream signalling. In this regard, metformin has an advantage over other AMPK activators for the treatment of renal fibrosis. © 2017 John Wiley & Sons Australia, Ltd

Feng H.,Peking University | Feng H.,Key Laboratory of Molecular Cardiovascular science | Feng H.,Beijing Key Laboratory of Cardiovascular Receptors Research | Wang J.-Y.,Peking University | And 17 more authors.
Experimental Cell Research | Year: 2016

C1q/tumor necrosis factor-related protein-3 (CTRP3) is an adipokine with modulation effects on metabolism and inflammation. Adenosine triphosphate (ATP) exerts multiple biological effects in vascular smooth muscle cells (VSMCs) and energy imbalance is involved in vascular diseases. This study aimed to explore the effect of CTRP3 on energy production and its underlying mechanism in VSMCs. Our results indicated that exogenous CTRP3 increased ATP synthesis and the protein expression of oxidative phosphorylation (OXPHOS)-related molecules, including peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, sirtuin-3 (SIRT3), complex I, II, III, and V in cultured VSMCs. Depletion of endogenous CTRP3 by small interfering RNA (siRNA) reduced ATP synthesis and the expression of those molecules. PGC-1α knockdown abrogated CTRP3-induced ATP production and OXPHOS-related protein expression. Furthermore, CTRP3 increased mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential level. Pretreatment with N-acetyl-L-cysteine, a reactive oxygen species scavenger, and cyanidem-chlorophenylhydrazone, an uncoupler of OXPHOS, suppressed CTRP3-induced ROS production, PGC-1α expression and ATP synthesis. In conclusion, CTRP3 modulates mitochondrial energy production through targets of ROS and PGC-1α in VSMCs. © 2016 Elsevier Inc.

Wang X.-Y.,Peking University | Wang X.-Y.,Beijing Key Laboratory of Cardiovascular Receptors Research | Yu H.-Y.,Peking University | Yu H.-Y.,Beijing Key Laboratory of Cardiovascular Receptors Research | And 12 more authors.
Thrombosis Research | Year: 2015

Introduction Mean platelet volume (MPV) is related to the reactivity of platelets. Among survivors of acute myocardial infarction (MI), greater MPV is known to be associated with impaired reperfusion and higher mortality. The aims of the study is to investigate the dynamic changes of MPV and the relation between MPV and cardiac function in patients with acute MI and received primary percutaneous coronary intervention (PCI). Materials and Methods This retrospective cohort study included patients presented during January 2008 to March 2011 to Peking University Third Hospital with ST-segment elevation MI. All patients received successful PCI. MPV was measured serially, using a Sysmex XE2100 haematology analyser, from admission to day-7 after MI. Results In 375 patients, MPV was at its highest value (10.2 ± 1.0 fL) and correlated well with platelet distribution width (PDW, r = 0.833, p < 0.0001) at the admission, and then reduced by 16% within the 24 hours, together with marked weakening of its correlation with PDW. Patients with poorer ventricular function, estimated by high Killip Class ( 2, n = 96), had higher MPV values at all-time points. By logistic regression model and after adjusting for related confounders, high MPV remained as an independent predictor of Killip Class 2 (OR 1.873, CI 95% 1.373 - 2.673, p = 0.001). Clopidogrel pre-usage resulted in significant MPV reduction on admission. Conclusions MPV undergoes rapid and dynamic changes during the acute phase of MI, and was higher in patients with high Killip Class, suggesting a predictive value of MPV in ventricular dysfunction and clinical outcome of acute phase of MI. © 2015 Elsevier Ltd.

Wang X.,Peking University | Wang X.,Beijing Key Laboratory of Cardiovascular Receptors Research | Yu H.,Peking University | Yu H.,Beijing Key Laboratory of Cardiovascular Receptors Research | And 8 more authors.
Mediators of Inflammation | Year: 2014

Inflammation plays an important role in plaque development and left ventricular remodeling during acute myocardial infarction (AMI). Clopidogrel may exhibit some anti-inflammatory properties and high loading dose of clopidogrel results in improved clinical outcomes in patients with AMI. 357 patients who received successful primary percutaneous coronary intervention from January 2008 to March 2011 in Peking University Third Hospital were included in this study. Different loading dose of clopidogrel (300 mg, 450 mg, or 600 mg) was given at the discretion of the clinician. Neutrophils reached their peak values on the first day after AMI. Higher levels of peak neutrophil and lower left ventricular ejection fraction (LVEF) were found in patients of low clopidogrel loading dose group (300 mg or 450 mg). After adjusting for the related confounders, a logistic regression model showed that low clopidogrel loading dose remained an independent predictor of low LVEF (LVEF ≤ 50%) [OR: 1.97, 95% CI: 1.03-3.79, P = 0.04]. Low clopidogrel loading dose was associated with higher peak neutrophil count and poor left ventricular systolic function, suggesting an important role of clopidogrel loading dose in the improvement of left ventricular function and high loading dose may exhibit better anti-inflammatory properties. © 2014 Xinyu Wang et al.

Zhou Y.,Peking University | Zhou Y.,Beijing Key Laboratory of Cardiovascular Receptors Research | Zhang Y.,Peking University | Zhang Y.,Beijing Key Laboratory of Cardiovascular Receptors Research | And 5 more authors.
PLoS ONE | Year: 2014

Progression of chronic obstructive pulmonary disease is associated with small airway obstruction by accumulation of inflammatory mucous exudates. However, the mechanism of mucin hypersecretion after exposure to cigarette smoke (CS) is still not clear. In this study, we explored the contribution of β2-adrenoceptor (β2-AR) signaling to CS extract (CSE)-induced mucus hypersecretion in vitro and examined the effect of a β-blocker on airway mucin hypersecretion in vivo. NCI-H292 epithelial cell line was used to determine the contribution of β2-AR signaling to CSE-induced MUC5AC production by treatment with β2-AR antagonists propranolol and ICI118551 and β2-AR-targeted small interfering RNA. The effect of propranolol on airway mucus hypersecretion was examined in a rat model exposed to CS. MUC5AC expression was assayed by real-time PCR, immunohistochemistry and ELISA. β2-AR and its downstream signaling were detected by western blot analysis. We found that pretreating NCI-H292 cells with propranolol, ICI118551 for 30 min or β2AR-targeted siRNA for 48 h reduced MUC5AC mRNA and protein levels stimulated by CSE. However,inhibiting the classical β2AR- cAMP-PKA pathway didn't attenuate CSE-induced MUC5AC production, while silencing β-arretin2 expression significantly decreased ERK and p38MAPK phosphorylation, thus reduced the CSE-stimulated MUC5AC production. In vivo, we found that administration of propranolol (25 mg kg-1d-1) for 28 days significantly attenuated the airway goblet cell metaplasia, mucus hypersecretion and MUC5AC expression of rats exposed to CS. From the study, β2-AR-β-arrestin2-ERK1/2 signaling was required for CS-induced airway MUC5AC expression. Chronic propranolol administration ameliorated airway mucus hypersecretion and MUC5AC expression in smoking rats. The exploration of these mechanisms may contribute to the optimization of β2-AR target therapy in chronic obstructive pulmonary disease. © 2014 Zhou et al.

Zhou Y.,Peking University | Zhou Y.,Beijing Key Laboratory of Cardiovascular Receptors Research | Xu M.,Peking University | Xu M.,Beijing Key Laboratory of Cardiovascular Receptors Research | And 5 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2014

Beta-blockers, especially selective β1-adrenoceptor antagonists, are often used to treat cardiovascular disease, even when complicated by chronic obstructive pulmonary disease. The association of beta-blocker selectivity and treatment effects is disputed, and the curative effects and side-effects of various antagonists may differ. Herein we investigated the effects of 1 months treatment with the selective β1-adrenoceptor antagonist metoprolol and the non-selective β-adrenoceptor antagonist propranolol on pulmonary function and pathology in a 4-month rat model of passive cigarette smoke exposure and explored potential mechanisms of action. Lung function and general pathological changes were evaluated after 4 months exposure to cigarette smoke, with metoprolol and propranolol treatment (50 and 25 mg/kg per day, respectively; intragastrically) during the last month. Cytokine and mucin levels in bronchoalveolar lavage fluid (BALF) were determined by ELISA, whereas β1- and β2-adrenoceptor expression in the lungs was evaluated by immunohistochemistry and western blot analysis. Chronic treatment with metoprolol and propranolol did not exacerbate peak expiratory flow or intra-airway pressure in rats exposed to cigarette smoke. Propranolol significantly attenuated inflammatory cell infiltration, cytokine levels (tumour necrosis factor-α and interleukin-8) in BALF or mucus secretion, whereas metoprolol reduced only smooth muscle proliferation. Moreover, propranolol treatment was associated (albeit not significantly) with restoring β2-adrenoceptor expression in airway epithelia. Propranolol had a more beneficial effect on cigarette smoking-induced lung damage than metoprolol in a smoking rat model that may be associated with restoration of endogenous β2-adrenoceptor density in the airway epithelial cells. © 2014 Wiley Publishing Asia Pty Ltd.

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