title: SUV39H1 mediated SIRT1 trans-repression contributes to cardiac ischemia-reperfusion injury.
abstract: Ischemic reperfusion (I/R) contributes to deleterious cardiac remodeling and heart failure. The deacetylase SIRT1 has been shown to protect the heart from I/R injury. We examined the mechanism whereby I/R injury represses SIRT1 transcription in the myocardium. There was accumulation of trimethylated histone H3K9 on the proximal SIRT1 promoter in the myocardium in mice following I/R injury and in cultured cardiomyocytes exposed to hypoxia-reoxygenation (H/R). In accordance, the H3K9 trimethyltransferase SUV39H1 bound to the SIRT1 promoter and repressed SIRT1 transcription. SUV39H1 expression was up-regulated in the myocardium in mice following I/R insults and in H/R-treated cardiomyocytes paralleling SIRT1 down-regulation. Silencing SUV39H1 expression or suppression of SUV39H1 activity erased H3K9Me3 from the SIRT1 promoter and normalized SIRT1 levels in cardiomyocytes. Meanwhile, SUV39H1 deficiency or inhibition attenuated I/R-induced infarction and improved heart function in mice likely through influencing ROS levels in a SIRT1-dependent manner. Therefore, our data uncover a novel mechanism for SIRT1 trans-repression during cardiac I/R injury and present SUV39H1 as a druggable target for the development of therapeutic strategies against ischemic heart disease.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Weng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Huan
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China. xdc77@aliyun.com.|Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Middle Rd, Shanghai, 200072, China. xdc77@aliyun.com.
authors.forename: Dachun
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Rd, Nanjing, 210029, Jiangsu, China. yjxu@njmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D056564:Sirtuin 1 / Q000096:biosynthesis*; D014158:Transcription, Genetic
chemical_list: D012097:Repressor Proteins; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Epigenetics; Ischemia–reperfusion injury; SIRT1; SUV39H1; Transcriptional regulation