SIRT1-mediated acute cardioprotection
SIRT1-mediated acute cardioprotection
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DOI：
10.1152/ajpheart.00587.2011
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发表时间：
2011-10-01
影响因子：
4.8
通讯作者：
Brookes, Paul S.
中科院分区：
文献类型：
--
作者：
Nadtochiy, Sergiy M.;Yao, Hongwei;Brookes, Paul S.
Nadtochiy SM，姚，McBurney MW，Gu W，Guarente L，Rahman I，Brookes PS。SIRT1介导的急性心脏保护作用。Am J Physiol心圈Physiol 301：H1506-H1512,2011。首次发表于2011年8月19日；doi:10.1152/ajpheart.00587.2011.-Overexpression研究揭示了沉默的信息转录调节因子1(SIRT1)赖氨酸脱乙酰酶通过长期转录效应在心脏保护缺血再灌注损伤中的作用。然而，在急性心脏保护的背景下，短期SIRT1介导的赖氨酸去乙酰化作用还知之甚少。本研究利用SIRT1缺陷(SIRT1(+/-))和SIRT1过表达(SIRT1(+))小鼠，研究了SIRT1在第一窗缺血预适应(IPC)急性心肌保护机制中的作用。在野生型心脏中，在IPC期间观察到胞浆赖氨酸去乙酰化，并在药物抑制SIRT1后观察到过度乙酰化。与SIRT1在IPC中的作用一致，SIRT1(+/-)心脏不能被预适应，并表现出胞浆赖氨酸乙酰化增加。此外，SIRT1(+)心脏对缺血再灌注损伤有内源性保护作用，胞浆乙酰化程度降低。在SIRT1(+)小鼠中，这两种作用均可被急性时间尺度上的药物抑制SIRT1逆转。检测了SIRT1的几个下游靶点，数据表明内皮型一氧化氮合酶磷酸化、核因子-kappaB和刺激自噬可能起到了作用。综上所述，这些数据表明，SIRT1作用于非转录靶点是急性IPC心肌保护所必需的，依赖SIRT1的赖氨酸去乙酰化发生在IPC过程中，可能在心脏保护信号中发挥作用。
Nadtochiy SM, Yao H, McBurney MW, Gu W, Guarente L, Rahman I, Brookes PS. SIRT1-mediated acute cardioprotection. Am J Physiol Heart Circ Physiol 301: H1506-H1512, 2011. First published August 19, 2011; doi:10.1152/ajpheart.00587.2011.-Overexpression studies have revealed a role for silent information regulator of transcription 1 (SIRT1) lysine deacetylase in cardioprotection against ischemia-reperfusion injury via long-term transcriptional effects. However, short-term SIRT1-mediated lysine deacetylation, within the context of acute cardioprotection, is poorly understood. In this study, the role of SIRT1 in the acute cardioprotective paradigm of first window ischemic preconditioning (IPC) was studied using SIRT1-deficient (SIRT1(+/-)) and SIRT1-overexpressing (SIRT1(+++)) mice. In wild-type hearts, cytosolic lysine deacetylation was observed during IPC, and overacetylation was observed upon pharmacological SIRT1 inhibition. Consistent with a role for SIRT1 in IPC, SIRT1(+/-) hearts could not be preconditioned and exhibited increased cytosolic lysine acetylation. Furthermore, SIRT1(+++) hearts were endogenously protected against ischemia-reperfusion injury and exhibited decreased cytosolic acetylation. Both of these effects in SIRT1(+++) mice were reversed by pharmacological SIRT1 inhibition on an acute timescale. Several downstream targets of SIRT1 were examined, with data suggesting possible roles for endothelial nitric oxide synthase phosphorylation, NF-kappa B, and stimulation of autophagy. In conclusion, these data suggest that SIRT1, acting on nontranscriptional targets, is required for cardioprotection by acute IPC and that SIRT1-dependent lysine deacetylation occurs during IPC and may play a role in cardioprotective signaling.