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 (HP1 gamma) 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.
[1]Nanjing Med Univ, Dept Pathophysiol, Key Lab Cardiovasc Dis & Mol Intervent, Nanjing 211166, Jiangsu, Peoples R China.
[2]Nanjing Med Univ, Dept Pathophysiol, Key Lab Human Funct Genom Jiangsu Prov, Nanjing 211166, Jiangsu, Peoples R China.
[3]Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Shanghai 200032, Peoples R China.
[4]Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China.
[5]Jiangsu Jiankang Vocat Coll, Dept Nursing, Nanjing 210029, Jiangsu, Peoples R China.
[6]Max Planck Inst Immunobiol & Epigenet, Dept Epigenet, Stubeweg 51, D-79108 Freiburg, Germany.
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