title: β-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression.
abstract: Oxidative stress is a causal factor and key promoter of a variety of cardiovascular diseases associated with apoptotic cell death by causing deregulation of related genes. Though carvedilol, a β-adrenergic blocker, has been shown to produce cytoprotective effects against cardiomyocyte apoptosis, the mechanisms are not fully understood. The present study was designed to investigate whether the beneficial effects of carvedilol are related to microRNAs which have emerged as critical players in cardiovascular pathophysiology via post-transcriptional regulation of protein-coding genes. In vivo, we demonstrated that carvedilol ameliorated impaired cardiac function of infarct rats and restored miR-133 expression. In vitro, carvedilol protected cardiomyocytes from H2O2 induced apoptosis detected by TUNEL staining and MTT assays, and increased miR-133 expression in cardiomyocytes. Overexpression of miR-133, a recognized anti-apoptotic miRNA, produced similar effects to carvedilol: reduction of reactive oxygen species (ROS) and malondialdehyde (MDA) content and increment of superoxide dismutase (SOD) activity and glutathione peroxidase (GPx) level, so as to protect cardiomyocytes from apoptosis by downregulating caspase-9 and caspase-3 expression in the presence of H2O2. Transfection with AMO-133 (antisense inhibitor oligodeoxyribonucleotides) alone abolished the beneficial effects of carvedilol. Caspase-9-specific inhibitor z-LEHD-fmk, caspase-3-specific inhibitor z-DEVD-fmk, caspase-9 siRNA and caspase-3 siRNA were used to establish caspase-3 as a downstream target of miR-133. In conclusion, our data indicated that carvedilol protected cardiomyocytes by increasing miR-133 expression and suppressing caspase-9 and subsequent apoptotic pathways.
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China.
authors: Chaoqian
authors: C
authors: Xu
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Yingying
authors: Y
authors: Hu
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Liangyu
authors: L
authors: Hou
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Jin
authors: J
authors: Ju
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Xiaoguang
authors: X
authors: Li
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Ning
authors: N
authors: Du
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Xiaoxiang
authors: X
authors: Guan
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Zhenhong
authors: Z
authors: Liu
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, China.
authors: Tianze
authors: T
authors: Zhang
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Wei
authors: W
authors: Qin
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Nannan
authors: N
authors: Shen
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
authors: Muhammad U
authors: MU
authors: Bilal
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China.
authors: Yanjie
authors: Y
authors: Lu
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: hmuzhangyong@hotmail.com.
authors: Yong
authors: Y
authors: Zhang
authors: Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: shanhongli@ems.hrbmu.edu.cn.
authors: Hongli
authors: H
authors: Shan
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000494:pharmacology; D000077261:Carvedilol; D053453:Caspase 9 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006334:Heart Function Tests; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002316:Cardiotonic Agents; C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D011412:Propanolamines; D000077261:Carvedilol; D006861:Hydrogen Peroxide; D053453:Caspase 9
keywords: Apoptosis; Carvedilol; Caspase-3; Caspase-9; Oxidative stress; miR-133