Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Nat Commun. 2017 Mar 31;8:14941. doi: 10.1038/ncomms14941.
Myocardial infarction (MI) dampens heart function and poses a great health risk. The class III deacetylase sirtuin 1 (SIRT1) is known to confer cardioprotection. SIRT1 expression is downregulated in the heart by a number of stress stimuli that collectively drive the pathogenesis of MI, although the underlying mechanism remains largely obscure. Here we show that in primary rat neonatal ventricular myocytes (NRVMs), ischaemic or oxidative stress leads to a rapid upregulation of SUV39H, the mammalian histone H3K9 methyltransferase, paralleling SIRT1 downregulation. Compared to wild-type littermates, SUV39H knockout mice are protected from MI. Likewise, suppression of SUV39H activity with chaetocin attenuates cardiac injury following MI. Mechanistically, SUV39H cooperates with heterochromatin protein 1 gamma (HP1γ) to catalyse H3K9 trimethylation on the SIRT1 promoter and represses SIRT1 transcription. SUV39H augments intracellular ROS levels in a SIRT1-dependent manner. Our data identify a previously unrecognized role for SUV39H linking SIRT1 trans-repression to myocardial infarction.
心肌梗死（MI）会削弱心脏功能，带来严重的健康风险。III 类去乙酰化酶沉默调节蛋白 1（SIRT1）被认为具有心脏保护作用。许多应激刺激会导致 SIRT1 在心脏中的表达下调，这些应激刺激共同驱动 MI 的发病机制，但其中的潜在机制在很大程度上仍不清楚。在这里，我们发现在原代大鼠新生心室肌细胞（NRVM）中，缺血或氧化应激会导致哺乳动物组蛋白 H3K9 甲基转移酶 SUV39H 的快速上调，与 SIRT1 的下调平行。与野生型同窝仔相比，SUV39H 敲除小鼠对 MI 具有保护作用。同样，用 chaetocin 抑制 SUV39H 活性可减轻 MI 后的心脏损伤。从机制上讲，SUV39H 与异染色质蛋白 1 伽马（HP1γ）合作，在 SIRT1 启动子上催化 H3K9 三甲基化，并抑制 SIRT1 的转录。SUV39H 以依赖 SIRT1 的方式增加细胞内 ROS 水平。我们的数据确定了 SUV39H 的一个以前未被识别的作用，它将 SIRT1 的反式抑制与心肌梗死联系起来。
