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

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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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (30871017, 31071001 and 31271226 to Dr. W Jiang).

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Authors and Affiliations

  1. Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Xiao-Xiao Wang, Xu-Lei Wang, Ming-ming Tong, Lu Gan, Huali Chen, Si-si Wu, Jia-Xiang Chen, Ru-Li Li, Yao Wu & Wei Jiang

  2. School of Life Sciences and Bioengineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People’s Republic of China

    Xu-Lei Wang

  3. Department of Cardiology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People’s Republic of China

    Heng-yu Zhang & Ye Zhu

  4. Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China

    Yan-xin Li

  5. Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    Meijing Wang

  6. Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Jin-han He

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  1. Xiao-Xiao Wang
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395_2016_531_MOESM1_ESM.tif

Supplementary Figure I. Effect of sirt6 on I/R injury in cardiac tissues and H/R damage in cardiomyocytes. A. L-lactate dehydrogenase (LDH), creatine kinase (CK) and MB isoenzyme of CK (CK-MB) activities in plasma of WT and SIRT6+/− mice 24 hours after I/R (n = 10/group). B-D. LDH, CK and CK-MB activities in perfusates of isolated WT and SIRT6+/− mouse hearts (n = 10/group), respectively. E and F. LDH, CK and CK-MB activities in cultural supernatants of mock or sirt6-siRNA transfected, or Ad-null or Ad-SIRT6 infected cardiomyocytes with 8 h of hypoxia followed by 2 h of reoxygenation (n = 7/group), respectively. G-I. LDH, CK and CK-MB activities in plasma of Ad-null or Ad-SIRT6 infected WT and SIRT6+/− mice 24 hours after I/R (n = 10/group). J-L. LDH, CK and CK-MB activities in cultural supernatants of mock or sirt6-siRNA transfected cardiomyocytes in the absence and presence of 10 µmol/L compound C or FoxO3α siRNA with 8 h of hypoxia followed by 2 h of reoxygenation (n = 7/group), respectively. Cardiac enzyme activities in plasma and cell culture supernatants were statistically analyzed with the one-way ANOVA, and in perfusates of isolated hearts with the unpaired Student’s t-test. *P < 0.05, **P < 0.01; in Figure B-D, *P < 0.05, **P < 0.01 vs WT control. (TIFF 11840 kb)

395_2016_531_MOESM2_ESM.tif

Supplementary Figure II. Effect of sirt6 on Left Ventricular Remodeling 4 weeks after cardiac I/R injury. A. Histomorphological appearance and remodeling of the LV 4 weeks after I/R. Hearts were sectioned at the level of the papillary muscles, and stained with Masson’s trichrome (the up panels, scale bar = 20 μm; the bottom panels, scale bar = 1 mm). B and C. Morphometric analysis of LV fibrosis (C) and wall thinning (D) in WT and SIRT6+/− animals (n = 6/group), respectively. D. Representative M-mode frames from the mid-papillary region of sham WT (a) and SIRT6+/− (c) mice, as well as infracted WT (b) and SIRT6+/− (d) mice 4 weeks after acute I/R injury. Yellow arrow indicates width of the LV chamber. LV fibrosis was statistically analyzed with the one-way ANOVA, and wall thinning with the unpaired Student’s t-test. *P < 0.05, **P < 0.01 (TIFF 18698 kb)

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Wang, XX., Wang, XL., Tong, Mm. et al. SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms. Basic Res Cardiol 111, 13 (2016). https://doi.org/10.1007/s00395-016-0531-z

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