Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy

Jie Li, Wenxia Ma, Guihua Yue, Yao Liang Tang, Il-man Kim, Neal Lee Weintraub, Xuejun Wang, Huabo Su

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background 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. Methods and results 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)53-60
Number of pages8
JournalJournal of molecular and cellular cardiology
Volume102
DOIs
StatePublished - Jan 1 2017

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Diabetic Cardiomyopathies
Proteasome Endopeptidase Complex
Ubiquitin
Experimental Diabetes Mellitus
Proteins
Takotsubo Cardiomyopathy
Eukaryotic Cells
Streptozocin
Type 1 Diabetes Mellitus
Cardiac Myocytes
Quality Control
Transgenic Mice
Lysine
Heart Diseases
Collagen

Keywords

  • Diabetic cardiomyopathy
  • PA28α
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy. / Li, Jie; Ma, Wenxia; Yue, Guihua; Tang, Yao Liang; Kim, Il-man; Weintraub, Neal Lee; Wang, Xuejun; Su, Huabo.

In: Journal of molecular and cellular cardiology, Vol. 102, 01.01.2017, p. 53-60.

Research output: Contribution to journalArticle

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