title: Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy.
abstract: Defect in mitochondrial biogenesis and cardiac energy metabolism is a critical contributing factor to cardiac hypertrophy and heart failure. Sentrin/SUMO specific protease 1 (SENP1) mediated regulation of PGC-1α transcriptional activity plays an essential role in mitochondrial biogenesis and mitochondrial function. However, whether SENP1 plays a role in cardiac hypertrophy and failure is unknown. We investigated whether alteration in SENP1 expression affects cardiomyopathy and the underlying mechanism. In our present study, we found that the expression of SENP1 was induced in mouse and human failing hearts associated with induced expression of mitochondrial genes. SENP1 expression in cardiomyocytes was induced by hypertrophic stimuli through calcium/calcineurin-NFAT3. SENP1 regulated mitochondrial gene expression by de-SUMOylation of MEF-2C, which enhanced MEF-2C-mediated PGC-1α transcription. Genetic induction of SENP1 led to mitochondrial dysregulation and cardiac dysfunction in vivo. Our data showed that pathogenesis of cardiomyopathy is attributed by SENP1 mediated regulation of mitochondrial abnormities. SENP1 up-regulation in diseased heart is mediated via calcineurin-NFAT/MEF2C-PGC-1α pathway.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Cai
authors.affiliation: Shanghai Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Shanghai Ninth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Mei
authors.affiliation: Texas Heart Institute/St. Lukes' Episcopal Hospital, Houston, TX, USA; Department of Cardiology, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Shanghai Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Texas Heart Institute/St. Lukes' Episcopal Hospital, Houston, TX, USA; Department of Cardiology, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jkcheng@shsmu.edu.cn.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D050778:NFATC Transcription Factors / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D050778:NFATC Transcription Factors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D019703:Calcineurin; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse
keywords: Calcium/calcineurin-NFAT3; Cardiac hypertrophy; MEF-2C; Mitochondria; PGC-1α; Sentrin/SUMO specific protease 1 (SENP1)