title: Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy.
abstract: Diabetic cardiomyopathy is a major risk factor in diabetic patients but its pathogenesis remains poorly understood. The ubiquitin-proteasome system (UPS) facilitates protein quality control by degrading unnecessary and damaged proteins in eukaryotic cells, and dysfunction of UPS is implicated in various cardiac diseases. However, the overall functional status of the UPS and its pathophysiological role in diabetic cardiomyopathy have not been determined.
  
  
  
  Type I diabetes was induced in wild-type and transgenic mice expressing a UPS functional reporter (GFPdgn) by injections of streptozotocin (STZ). STZ-induced diabetes progressively impaired cardiac UPS function as evidenced by the accumulation of GFPdgn proteins beginning two weeks after diabetes induction, and by a buildup of total and lysine (K) 48-linked polyubiquitinated proteins in the heart. To examine the functional role of the UPS in diabetic cardiomyopathy, cardiac overexpression of PA28α (PA28αOE) was used to enhance proteasome function in diabetic mouse hearts. PA28αOE diabetic mice displayed exhibited restoration of cardiac UPS function, as demonstrated by the diminished accumulation of GFPdgn and polyubiquitinated proteins. Moreover, PA28αOE diabetic mice exhibited reduced myocardial collagen deposition, decreased cardiomyocyte apoptosis, and improved cardiac systolic and diastolic function.
  
  
  
  Impairment of cardiac UPS function is an early event in STZ-induced diabetes. Overexpression of PA28α attenuates diabetes-induced proteotoxic stress and cardiomyopathy, suggesting a potential therapeutic role for enhancement of cardiac proteasome function in this disorder.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States; Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Ma
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States; Department of Cardiology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Yue
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors.forename: Yaoliang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors.forename: Il-Man
authors.initials: IM
authors.lastname: Kim
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States; Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States.. Electronic address: HSU@augusta.edu.
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression; D017930:Genes, Reporter; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse
keywords: Diabetic cardiomyopathy; PA28α; Proteasome; Ubiquitin