title: Involvement of activated SUMO-2 conjugation in cardiomyopathy.
abstract: Sumoylation is a posttranslational modification that regulates a wide spectrum of cellular activities. Cardiomyopathy is the leading cause of heart failure. Whether sumoylation, particularly SUMO-2/3 conjugation, is involved in cardiomyopathy has not been investigated. We report here that SUMO-2/3 conjugation was elevated in the human failing hearts, and we investigated the impact of increased SUMO-2 conjugation on heart function by using the gain-of-function approach in mice, in which cardiac specific expression of constitutively active SUMO-2 was governed by alpha myosin heavy chain promoter (MHC-SUMO-2 transgenic, SUMO-2-Tg). Four of five independent SUMO-2-Tg mouse lines exhibited cardiomyopathy with various severities, ranging from acute heart failure leading to early death to the development of chronic cardiomyopathy with aging. We further revealed that SUMO-2 directly regulated apoptotic process by at least partially targeting calpain 2 and its natural inhibitor calpastatin. SUMO conjugation to calpain 2 promoted its enzymatic activity, and SUMO attachment to calpastatin mainly promoted its turnover and altered its subcellular distribution. Thus, enhanced SUMO-2 conjugation led to increased apoptosis and played a pathogenic role in the development of cardiomyopathy and heart failure.
authors: 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: Eun Young
authors: EY
authors: Kim
authors: In Vitro Fertilization Center, Affiliated Hospital of Hainan Medical University, 31 Long-Hua Road, Haikou, Hainan 570102, People's Republic of China.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA.
authors: Bo
authors: B
authors: Ye
authors: Department of Cardiac Pathology, Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Avenue, MC 2-255, Houston, TX 77030, USA.
authors: Ana Maria
authors: AM
authors: Segura
authors: 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: Ilimbek
authors: I
authors: Beketaev
authors: Laboratory of 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: Yutao
authors: Y
authors: Xi
authors: Department of Biochemistry and Molecular Biology, University of Houston, Houston, TX 77204, USA.
authors: Wei
authors: W
authors: Yu
authors: 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: Jiang
authors: J
authors: Chang
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA.
authors: Faqian
authors: F
authors: Li
authors: 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: Jun
authors: J
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism*; D006367:HeLa Cells; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C117909:SUMO2 protein, human; C515972:SUMO2 protein, mouse; D025841:Small Ubiquitin-Related Modifier Proteins; C117908:Sumo3 protein, mouse; D014452:Ubiquitins; C033668:calpastatin; D002154:Calpain
keywords: Apoptosis; Calpain 2; Calpastatin; Cardiomyopathy; SUMO