title: Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction.
abstract: Sumoylation is a posttranslational modification implicated in a variety of cellular activities, and its role in a number of human pathogeneses such as cleft lip/palate has been well documented. However, the importance of the SUMO conjugation pathway in cardiac development and functional disorders is newly emerging. We previously reported that knockout of SUMO-1 in mice led to congenital heart diseases (CHDs). To further investigate the effects of imbalanced SUMO conjugation on heart development and function and its underlying mechanisms, we generated transgenic (Tg) mice with cardiac-specific expression of SENP2, a SUMO-specific protease that deconjugates sumoylated proteins, to evaluate the impact of desumoylation on heart development and function. Overexpression of SENP2 resulted in premature death of mice with CHDs-atrial septal defects (ASDs) and/or ventricular septal defects (VSDs). Immunobiochemistry revealed diminished cardiomyocyte proliferation in SENP2-Tg mouse hearts compared with that in wild type (WT) hearts. Surviving SENP2-Tg mice showed growth retardation, and developed cardiomyopathy with impaired cardiac function with aging. Cardiac-specific overexpression of the SUMO-1 transgene reduced the incidence of cardiac structural phenotypes in the sumoylation defective mice. Moreover, cardiac overexpression of SENP2 in the mice with Nkx2.5 haploinsufficiency promoted embryonic lethality and severity of CHDs, indicating the functional interaction between SENP2 and Nkx2.5 in vivo. Our findings indicate the indispensability of a balanced SUMO pathway for proper cardiac development and function. This article is part of a Special Issue entitled 'Post-translational Modification SI'.
authors.affiliation: Program in Genes and Development, The University of Texas Health Science Center at Houston, USA.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors / Q000235:genetics; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D025842:SUMO-1 Protein; D014157:Transcription Factors; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human