Let-7a regulates expression of &#x03B2; 1 -adrenoceptors and forms a negative feedback circuit with the &#x03B2; 1 -adrenoceptor signaling pathway in chronic ischemic heart failure

Yue Du; Mingyu Zhang; Wei Zhao; You Shu; Ming Gao; Yanan Zhuang; Ti Yang; Wei Mu; Tingting Li; Xin Li; Fei Sun; Zhenwei Pan; Yanjie Lu

doi:10.18632/oncotarget.14436

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Research Papers:

Let-7a regulates expression of β₁-adrenoceptors and forms a negative feedback circuit with the β₁-adrenoceptor signaling pathway in chronic ischemic heart failure

Yue Du, Mingyu Zhang, Wei Zhao, You Shu, Ming Gao, Yanan Zhuang, Ti Yang, Wei Mu, Tingting Li, Xin Li, Fei Sun, Zhenwei Pan _ and Yanjie Lu

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Oncotarget. 2017; 8:8752-8764. https://doi.org/10.18632/oncotarget.14436

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Abstract

Yue Du1,*, Mingyu Zhang1,*, Wei Zhao1, You Shu1, Ming Gao1, Yanan Zhuang1, Ti Yang1, Wei Mu1, Tingting Li1, Xin Li1, Fei Sun1, Zhenwei Pan1, Yanjie Lu1,2

1Department 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

2Northern 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: [email protected]

Zhenwei Pan, email: [email protected]

Keywords: chronic ischemia heart failure, let-7a, β₁-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 β₁-adrenoceptors (β₁-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. β₁-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 β₁-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 β₁-AR level by CIHF and the effect was reversed by len-AMO-let-7a. Len-negative control did not produce any significant influence on β₁-AR expression. Importantly, there exists a negative feedback loop associated with β₁-AR regulation through β₁-AR/cAMP/PKA/GATA4/let-7a/β₁-AR signaling pathway in CIHF. As demonstrated, GATA4 was activated by β₁-AR up-regulation through cAMP-PKA signaling pathway in early phase of ischemia, then GATA4 positively regulated let-7a expression which in turn suppressed β₁-AR expression.

Conclusions: Let-7a regulates β₁-AR expression and forms a negative feedback loop with β₁-AR signaling pathway in ischemic heart failure. This study provides a new insight into the differential expression of β₁-AR in early and later phase of myocardial ischemia.

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Research Papers:

Let-7a regulates expression of β1-adrenoceptors and forms a negative feedback circuit with the β1-adrenoceptor signaling pathway in chronic ischemic heart failure

Abstract

Let-7a regulates expression of β₁-adrenoceptors and forms a negative feedback circuit with the β₁-adrenoceptor signaling pathway in chronic ischemic heart failure