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SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms.
Wang, Xiao-Xiao; Wang, Xu-Lei; Tong, Ming-ming; Gan, Lu; Chen, Huali; Wu, Si-si; Chen, Jia-Xiang; Li, Ru-Li; Wu, Yao; Zhang, Heng-yu; Zhu, Ye; Li, Yan-xin; He, Jin-han; Wang, Meijing; Jiang, Wei.
Afiliação
  • Wang XX; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Wang XL; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Tong MM; School of Life Sciences and Bioengineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China.
  • Gan L; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Chen H; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Wu SS; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Chen JX; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Li RL; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Wu Y; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Zhang HY; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Zhu Y; Department of Cardiology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People's Republic of China.
  • Li YX; Department of Cardiology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People's Republic of China.
  • He JH; Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Chengdu, People's Republic of China.
  • Wang M; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
  • Jiang W; Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Basic Res Cardiol ; 111(2): 13, 2016 Mar.
Article em En | MEDLINE | ID: mdl-26786260
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Traumatismo por Reperfusão Miocárdica / Sirtuínas / Fatores de Transcrição Forkhead Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Traumatismo por Reperfusão Miocárdica / Sirtuínas / Fatores de Transcrição Forkhead Idioma: En Ano de publicação: 2016 Tipo de documento: Article