SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms
SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms
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DOI：
10.1007/s00395-016-0531-z
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发表时间：
2016-03-01
影响因子：
9.5
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Wang, Xiao-Xiao;Wang, Xu-Lei;Jiang, Wei
SIRT6 是 NAD(+) 依赖性 III 类脱乙酰酶 Sirtuin 家族的成员，已被证明在促进细胞抵抗氧化应激方面发挥重要作用。活性氧（ROS）的形成和氧化应激是心脏缺血/再灌注（I/R）损伤中细胞损伤和功能障碍的关键机制，但 SIRT6 在 I/R 诱导的 ROS 和氧化应激中的作用尚不清楚。在本研究中，我们通过使用杂合子SIRT6敲除（SIRT6（+/-））小鼠和培养的新生心肌细胞模型，研究了SIRT6如何介导I/R期间的氧化应激和心肌损伤。 SIRT6的部分敲除（KO）会加重心肌I/R小鼠的心肌损伤、心室重塑和氧化应激，而通过直接向心脏注射编码SIRT6的腺病毒构建体来恢复SIRT6表达可逆转SIRT6 KO对缺血心脏的这些有害影响。此外，在 Langendorff 灌注模型中，SIRT6 基因的部分缺失会降低 I/R 后心肌功能的恢复。同样，在缺氧/复氧后培养的心肌细胞中也观察到了 SIRT6 的保护作用。有趣的是，SIRT6 被发现上调 AMP/ATP，然后激活腺苷 5'-单磷酸激活蛋白激酶 (AMPK)-叉头盒 O3 α (FoxO3 α) 轴，并进一步启动下游抗氧化剂编码基因表达（锰超氧化物歧化酶和过氧化氢酶），从而降低细胞水平 氧化应激和介导缺血心脏的心脏保护作用。这些结果表明，SIRT6 通过 AMP/ATP 诱导的 AMPK 依赖性方式在缺血心脏中激活 FoxO3 α，从而保护心脏免受 I/R 损伤，从而上调抗氧化剂并抑制氧化应激。
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)-fork-head box O3 alpha (FoxO3 alpha) 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 FoxO3 alpha activation in the ischemic heart in an AMP/ATP-induced AMPK-dependent way, thus upregulating antioxidants and suppressing oxidative stress.