Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1506-12. doi: 10.1152/ajpheart.00587.2011. Epub 2011 Aug 19.
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-κB, 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.
过表达研究表明，沉默信息调节因子 1（SIRT1）赖氨酸去乙酰化酶在缺血再灌注损伤的心脏保护中具有作用，是通过长期的转录效应实现的。然而，在急性心脏保护的背景下，短期的 SIRT1 介导的赖氨酸去乙酰化作用还知之甚少。在这项研究中，使用 SIRT1 缺陷型（SIRT1(+/-)）和 SIRT1 过表达型（SIRT1(+++)）小鼠研究了 SIRT1 在急性第一窗口缺血预处理（IPC）心脏保护范例中的作用。在野生型心脏中，观察到 IPC 期间胞质赖氨酸去乙酰化，并且在药理学 SIRT1 抑制时观察到过度乙酰化。与 SIRT1 在 IPC 中的作用一致，SIRT1(+/-)心脏不能进行预处理，并表现出胞质赖氨酸乙酰化增加。此外，SIRT1(+++)心脏对缺血再灌注损伤具有内源性保护作用，并表现出胞质乙酰化减少。在 SIRT1(+++)小鼠中，这些效应都可以在急性时程上通过药理学 SIRT1 抑制来逆转。检查了 SIRT1 的几个下游靶标，数据表明内皮型一氧化氮合酶磷酸化、NF-κB 和自噬刺激可能具有作用。总之，这些数据表明，SIRT1 作为非转录靶点，在急性 IPC 的心脏保护中是必需的，并且 SIRT1 依赖性赖氨酸去乙酰化发生在 IPC 期间，可能在心脏保护信号转导中发挥作用。
