title: SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy.
abstract: Cardiomyopathy presents a major health issue and is a leading cause of heart failure. Although a subset of familial cardiomyopathy is associated with genetic mutations, over 50% of cardiomyopathy is defined as idiopathic, the mechanisms underlying which are under intensive investigation. SUMO conjugation is a dynamic posttranslational modification that can be readily reversed by the activity of sentrin-specific proteases (SENPs). However, whether SENPs are implicated in heart disease pathophysiology remains unexplored. We observed a significant increase in the level of SENP5, a SUMO isopeptidase, in human idiopathic failing hearts. To reveal whether it plays a role in the pathogenesis of cardiac muscle disorders, we used a gain-of-function approach to overexpress SENP5 in murine cardiomyocytes (SENP5 transgenic, SENP5-Tg). Overexpression of SENP5 led to cardiac dysfunction, accompanied by decreased cardiomyocyte proliferation and elevated apoptosis. The increase in apoptosis preceded other detectable pathological changes, suggesting its causal link to cardiomyopathy. Further examination of SENP5-Tg hearts unveiled a decrease in SUMO attachment to dynamin related protein (Drp1), a factor critical for mitochondrial fission. Correspondingly, the mitochondria of SENP5-Tg hearts at an early developmental stage were significantly larger compared with those in the control hearts, suggesting that desumoylation of Drp1 at least partially accounts for the cardiac phenotypes observed in the SENP5-Tg mice. Finally, overexpression of Bcl2 in SENP5-Tg hearts improved cardiac function of SENP5-Tg mice, further supporting the notion that SENP5 mainly targets mitochondrial function in vivo. Our findings demonstrate an important role of the desumoylation enzyme SENP5 in the development of cardiac muscle disorders, and point to the SUMO conjugation pathway as a potential target in the prevention/treatment of cardiomyopathy. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".
authors.affiliation: Center for Stem Cell Engineering, Department of Basic Research Laboratories, Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: In Vitro Fertilization Center, Affiliated Hospital of Hainan Medical University, 31 Long-Hua Road, Haikou, Hainan 570102, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell Engineering, Department of Basic Research Laboratories, Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA.
authors.forename: Ilimbek
authors.initials: I
authors.lastname: Beketaev
authors.affiliation: Department of Cardiovascular Pathology, Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Segura
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Houston, Houston, TX 77204, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Electrophysiology, Department of Basic Research Laboratories, Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Center for Molecular Development and Disease, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.affiliation: Center for Stem Cell Engineering, Department of Basic Research Laboratories, Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA. Electronic address: junwang@heart.thi.tmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D058207:Sumoylation
chemical_list: D010447:Peptide Hydrolases; C512579:Senp5 protein, human; D003546:Cysteine Endopeptidases; C439066:Senp2 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Apoptosis; Cardiomyopathy; Mitochondria; SENP5; SUMO