SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice.

Sai Ma,Yabin Wang,Miaomiao Fan,Bo Yang,Ran Zhang,Zuhong Tian,Jing Feng,Dong Han,Congye Li,Feng Cao,Xiang Li,Jiangwei Chen,Xiujuan Li

doi:10.1155/2017/4602715

Abstract

Background Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM. Methods and Results Cardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM). Conclusions Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM.

Highlights

Diabetes mellitus is an emerging threat to global human health
Myocardial hypertrophy in Diabetic cardiomyopathy (DCM) was evidenced by increased expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) (Figure 1(c))
For the first time, that cardiac-specific low expression of Silent information regulator 1 (SIRT1) caused both compromised insulin signaling and mitochondrial dynamic abnormity, contributing to phenotypes resembling DCM in the mouse heart

Summary

Introduction

Diabetes mellitus is an emerging threat to global human health. According to an official report, diabetes will affect approximately 400 million patients universally [1]. Diabetic cardiomyopathy (DCM) has been a major cause for increased morbidity and mortality in diabetic patients, contributing to over 50% diabetic death [2]. Mitochondrial dysfunction has recently been reported to be a major contributor to the development of DCM. Abundant evidence indicated that impaired mitochondrial biogenesis contributed to cardiac dysfunction in diabetic hearts [9]. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. SIRT1 may serve as a potential therapeutic target for DCM

Methods

Results

Discussion

Conclusion