Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:72302-72314. https://doi.org/10.18632/oncotarget.20305

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Abstract

Zhen-Zhou Zhang1,2,*, Yu-Wen Cheng1,*, Hai-Yan Jin1,3,*, Qing Chang1, Qian-Hui Shang4, Ying-Le Xu1, Lin-Xi Chen5, Ran Xu1, Bei Song1 and Jiu-Chang Zhong1,2

1State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China

2Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China

3Department of Mental Health, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

4Department of Cardiology and Institute of Clinical Medicine Research, Affiliated Hospital of Zunyi Medical College, Zunyi 563003, China

5Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China

*These authors contributed equally to this work

Correspondence to:

Jiu-Chang Zhong, email: [email protected], [email protected]

Keywords: SIRT6, angiotensin-converting enzyme 2, connective tissue growth factor, fibrosis, myocardial injury

Received: July 04, 2017     Accepted: July 26, 2017     Published: August 17, 2017

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.


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