Let-7a regulates expression of β 1 -adrenoceptors and forms a negative feedback circuit with the β 1 -adrenoceptor signaling pathway in chronic ischemic heart failure

// Yue Du 1, * , Mingyu Zhang 1, * , Wei Zhao 1 , You Shu 1 , Ming Gao 1 , Yanan Zhuang 1 , Ti Yang 1 , Wei Mu 1 , Tingting Li 1 , Xin Li 1 , Fei Sun 1 , Zhenwei Pan 1 , Yanjie Lu 1, 2 1 Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China 2 Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang 150081, P. R. China * These authors have contributed equally to this work Correspondence to: Yanjie Lu, email: yjlu2008@163.com Zhenwei Pan, email: panzw@ems.hrbmu.edu.cn Keywords: chronic ischemia heart failure, let-7a, β 1 -AR, GATA4 Received: October 02, 2016     Accepted: December 01, 2016     Published: January 02, 2017 ABSTRACT Background: The aim of the present study was to investigate the role of microRNA (miRNA) let-7a in down-regulation of β 1 -adrenoceptors (β 1 -AR) and elucidate the underlying mechanism of chronic ischemia heart failure (CIHF) in rats. Methods and Results: CIHF model was established by occlusion of coronary artery for 4 weeks. β 1 -AR level was obviously down-regulated and let-7a up-regulated in the failing heart 4 weeks after myocardial infarction. Overexpression of let-7a inhibited β 1 -AR expression in neonatal rat ventricular cells (NRVCs), which was abolished by anti-let-7a antisense inhibitor. The lentivirus vector containing precursor let-7a (len-pre-let-7a) further down-regulated the reduced β 1 -AR level by CIHF and the effect was reversed by len-AMO-let-7a. Len-negative control did not produce any significant influence on β 1 -AR expression. Importantly, there exists a negative feedback loop associated with β 1 -AR regulation through β 1 -AR/cAMP/PKA/GATA4/let-7a/β 1 -AR signaling pathway in CIHF. As demonstrated, GATA4 was activated by β 1 -AR up-regulation through cAMP-PKA signaling pathway in early phase of ischemia, then GATA4 positively regulated let-7a expression which in turn suppressed β 1 -AR expression. Conclusions: Let-7a regulates β 1 -AR expression and forms a negative feedback loop with β 1 -AR signaling pathway in ischemic heart failure. This study provides a new insight into the differential expression of β 1 -AR in early and later phase of myocardial ischemia.