title: SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms.
abstract: SIRT6, a member of the NAD(+)-dependent class III deacetylase sirtuin family, has been revealed to play important roles in promoting cellular resistance against oxidative stress. The formation of reactive oxygen species (ROS) and oxidative stress are the crucial mechanisms underlying cellular damage and dysfunction in cardiac ischemia/reperfusion (I/R) injury, but the role of SIRT6 in I/R-induced ROS and oxidative stress is poorly understood. In this study, by using heterozygous SIRT6 knockout (SIRT6(+/-)) mice and cultured neonatal cardiomyocyte models, we investigated how SIRT6 mediates oxidative stress and myocardial injury during I/R. Partial knockout (KO) of SIRT6 aggravated myocardial damage, ventricular remodeling, and oxidative stress in mice subjected to myocardial I/R, whereas restoration of SIRT6 expression by direct cardiac injection of adenoviral constructs encoding SIRT6 reversed these deleterious effects of SIRT6 KO in the ischemic heart. In addition, partial deletion of the SIRT6 gene decreased myocardial functional recovery following I/R in a Langendorff perfusion model. Similarly, the protective effects of SIRT6 were also observed in cultured cardiomyocytes following hypoxia/reoxygenation. Intriguingly, SIRT6 was noticed to up-regulate AMP/ATP and then activate the adenosine 5'-monophosphate-activated protein kinase (AMPK)-forkhead box O3α (FoxO3α) axis and further initiated the downstream antioxidant-encoding gene expression (manganese superoxide dismutase and catalase), thereby decreasing cellular levels of oxidative stress and mediating cardioprotection in the ischemic heart. These results suggest that SIRT6 protects the heart from I/R injury through FoxO3α activation in the ischemic heart in an AMP/ATP-induced AMPK-dependent way, thus upregulating antioxidants and suppressing oxidative stress.
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Xiao-Xiao
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.|School of Life Sciences and Bioengineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China.
authors.forename: Xu-Lei
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Ming-ming
authors.initials: MM
authors.lastname: Tong
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Huali
authors.initials: H
authors.lastname: Chen
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Si-si
authors.initials: SS
authors.lastname: Wu
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Jia-Xiang
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Ru-Li
authors.initials: RL
authors.lastname: Li
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Heng-yu
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Chengdu, People's Republic of China.
authors.forename: Yan-xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Jin-han
authors.initials: JH
authors.lastname: He
authors.affiliation: Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China. wcumsjw@scu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D020257:Ventricular Remodeling; D000099156:Superoxide Dismutase 2
chemical_list: D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D000975:Antioxidants; D002374:Catalase; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; D037761:Sirtuins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C499515:FOXO3 protein, rat; C474033:FoxO3 protein, mouse; C501860:Sirt6 protein, mouse; C560607:sirtuin 6, rat
keywords: Catalase; FoxO3α; Ischemia/reperfusion; Manganese superoxide dismutase; Oxidative stress; SIRT6