The sirtuin 6 prevents angiotensin II-mediated myocardial fibrosis and injury by targeting AMPK-ACE2 signaling

Zhen-Zhou Zhang,Ying-Le Xu,Yu-Wen Cheng,Bei Song,Qing Chang,Qian-Hui Shang,Jiu-Chang Zhong,Hai-Yan Jin,Lin-Xi Chen,Ran Xu

doi:10.18632/oncotarget.20305

Abstract

Sirtuin 6 (SIRT6) is an important modulator of cardiovascular functions in health and diseases. However, the exact role of SIRT6 in heart disease is poorly defined. We hypothesized that SIRT6 is a negative regulator of angiotensin II (Ang II)-mediated myocardial remodeling, fibrosis and injury. The male Sprague-Dawley rats were randomized to Ang II (200 ng/kg/min) infusion with an osmotic minipump and pretreated with recombinant plasmids adeno-associated viral vector (AAV)-SIRT6 (pAAV-SIRT6) or pAAV-GFP for 4 weeks. Ang II triggered downregulated levels of SIRT6 and angiotensin-converting enzyme 2 (ACE2) and upregulated expression of connective tissue growth factor (CTGF) and proinflammatory chemokine fractalkine (FKN), contributing to enhanced cardiac fibrosis and ultrastructural injury. Reduced levels of phosphorylated pAMPK-α, increased myocardial hypertrophy and impaired heart dysfunction were observed in both Ang II-induced hypertensive rats and ACE2 knockout rats, characterized with increases in heart weight and left ventricular (LV) posterior wall thickness and decreases in LV ejection fraction and LV fractional shortening. More importantly, pAAV-SIRT6 treatment strikingly potentiated cardiac levels of pAMPKα and ACE2 as well as decreased levels of CTGF, FKN, TGFβ1, collagen I and collagen III, resulting in alleviation of Ang II-induced pathological hypertrophy, myocardial fibrosis, cardiac dysfunction and ultrastructural injury in hypertensive rats. In conclusion, our findings confirmed cardioprotective effects of SIRT6 on pathological remodeling, fibrosis and myocardial injury through activation of AMPK-ACE2 signaling and suppression of CTGF-FKN pathway, indicating that SIRT6 functions as a partial agonist of ACE2 and targeting SIRT6 has potential therapeutic importance for cardiac fibrosis and heart disease.

Highlights

Heart failure is growing epidemic with high morbidity and mortality at an international scale [1, 2]
We firstly evaluated the effects of angiotensin II (Ang II) infusion on cardiac Sirtuin 6 (SIRT6) and angiotensin-converting enzyme 2 (ACE2) expression and myocardial hypertrophy
Ang II infusion led to marked increases in systolic blood pressure levels (Figure 1A) and downregulation of myocardial SIRT6 levels (Figure 1C) and ACE2 (Figure 1D) in the recombinant plasmids adenoassociated viral vector (AAV)-GFP-treated hypertensive rats associated with increased levels of plasma Ang II (Figure 1B)

Summary

Introduction

Heart failure is growing epidemic with high morbidity and mortality at an international scale [1, 2]. The sirtuin SIRT6, a conserved nicotinamide adenine dinucleotide-dependent protein deacetylase, plays critical roles in the regulation of cardiovascular functions, energy metabolism and aging [3,4,5]. Both single- and double-SIRT6 knockout mice develop significant cardiac hypertrophy, fibrosis and dysfunction [6]. We evaluated the effects of Ang II and ACE2 deficiency on SIRT6 levels and regulatory roles of SIRT6 in AMPK/ACE2 signaling and Ang II-mediated heart disease by the use of ACE2-mutant and Ang IIinfused hypertensive rats

Methods

Results

Conclusion