SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms

Xiao Xiao Wang, Xu Lei Wang, Ming ming Tong, Lu Gan, Huali Chen, Si si Wu, Jia Xiang Chen, Ru Li Li, Yao Wu, Heng yu Zhang, Ye Zhu, Yan xin Li, Jin han He, Meijing Wang, Wei Jiang

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Article number13
Pages (from-to)1-19
Number of pages19
JournalBasic Research in Cardiology
Volume111
Issue number2
DOIs
StatePublished - Mar 1 2016

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Reperfusion Injury
Cardiac Myocytes
Oxidative Stress
Antioxidants
Adenosine Monophosphate
Protein Kinases
Reperfusion
Reactive Oxygen Species
Ischemia
Adenosine Triphosphate
Myocardial Reperfusion
Ventricular Remodeling
Gene Deletion
Knockout Mice
NAD
Catalase
Superoxide Dismutase
Myocardial Ischemia
Up-Regulation
Perfusion

Keywords

  • Catalase
  • FoxO3α
  • Ischemia/reperfusion
  • Manganese superoxide dismutase
  • Oxidative stress
  • SIRT6

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

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.

In: Basic Research in Cardiology, Vol. 111, No. 2, 13, 01.03.2016, p. 1-19.

Research output: Contribution to journalArticle

Wang, XX, Wang, XL, Tong, MM, Gan, L, Chen, H, Wu, SS, Chen, JX, Li, RL, Wu, Y, Zhang, HY, Zhu, Y, Li, YX, He, JH, Wang, M & Jiang, W 2016, 'SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms', Basic Research in Cardiology, vol. 111, no. 2, 13, pp. 1-19. https://doi.org/10.1007/s00395-016-0531-z
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. / SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms. In: Basic Research in Cardiology. 2016 ; Vol. 111, No. 2. pp. 1-19.
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