Suppression of microRNA-16 protects against acute myocardial infarction by reversing beta2-adrenergic receptor down-regulation in rats
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Jiaqi Liu1,3,*, Fei Sun3,*, Yuying Wang1, Wanqi Yang1, Hongwen Xiao1, Yue Zhang1, Renzhong Lu1, Haixia Zhu1, Yuting Zhuang1, Zhenwei Pan1, Zhiguo Wang1, Zhimin Du2, Yanjie Lu1,3
1Department of Pharmacology State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, P.R. China
2Institute of Clinical Pharmacology of the Second Affiliated Hospital Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions, Harbin Medical University, Harbin, P.R. China
3Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, P.R. China
*These authors have contributed equally to this work
Yanjie Lu, email: [email protected]
Zhimin Du, email: [email protected]
Keywords: acute myocardial infarction, miR-16, beta2-adrenergic receptor, apoptosis
Received: November 30, 2016 Accepted: January 11, 2017 Published: February 16, 2017
microRNA-16 (miR-16) has been shown to be up-regulated in ischemic heart. Beta2-adrenoreceptor (β2-AR) exerts cardioprotective property in ischemic injury. This study aims to determine the effect of miR-16 in cardiac injury in rats and the possible involvement of β2-AR in this process. Acute myocardial infarction (AMI) model in rats was induced by ligation of left coronary artery. Neonatal rat ventricular cells (NRVCs) were cultured in vitro tests. The cardiomyocyte model of oxidative injury was mimicked by hydrogen peroxide. The expression of miR-16 was obviously up-regulated and β2-AR was remarkably down-regulated in both AMI rats and NRVCs under oxidative stress. miR-16 over-expression in NRVCs reduced cell viability and increased apoptosis. Conversely, inhibition of endogenous miR-16 with its specific inhibitor reversed these changes. Over-expression of miR-16 using an miR-16 lentivirus in AMI rats markedly increased cardiac infarct area, lactate dehydrogenase and creatine kinase activity, and exacerbated cardiac dysfunction. Lentivirus-mediated knockdown of miR-16 alleviated acute cardiac injury. Moreover, miR-16 over-expression significantly suppressed β2-AR protein expression in both cultured NRVCs and AMI rats, while inhibition of miR-16 displayed opposite effect on β2-AR protein expression. Luciferase assay confirmed that miR-16 could directly target the 3’untranslated region of β2-AR mRNA. miR-16 is detrimental to the infarct heart and suppression of miR-16 protects rat hearts from ischemic injury via up-regulating of β2-AR by binding to the 3’untranslated region of β2-AR gene. This study indicates that targeting miR-16/β2-AR axis may be a promising strategy for ischemic heart disease.
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