title: Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.
abstract: OBJECTIVE
  Recently we have shown that calpain-1 activation contributes to cardiomyocyte apoptosis induced by hyperglycemia. This study was undertaken to investigate whether targeted disruption of calpain would reduce myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.
  
  
  METHODS
  Diabetes in mice was induced by injection of streptozotocin (STZ), and OVE26 mice were also used as a type 1 diabetic model. The function of calpain was genetically manipulated by cardiomyocyte-specific knockout Capn4 in mice and the use of calpastatin transgenic mice. Myocardial hypertrophy and fibrosis were investigated 2 and 5 months after STZ injection or in OVE26 diabetic mice at the age of 5 months. Cultured isolated adult mouse cardiac fibroblast cells were also investigated under high glucose conditions.
  
  
  RESULTS
  Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes. Deficiency of Capn4 or overexpression of calpastatin reduced myocardial hypertrophy and fibrosis in both diabetic models, leading to the improvement of myocardial function. These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts. In cultured cardiac fibroblasts, high glucose-induced proliferation and MMP activities were prevented by calpain inhibition.
  
  
  CONCLUSIONS
  Myocardial hypertrophy and fibrosis in diabetic mice are attenuated by reduction of calpain function. Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy.
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhu
authors.forename: Manpreet
authors.initials: M
authors.lastname: Singh
authors.forename: David
authors.initials: D
authors.lastname: Hill
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.forename: J Malcolm
authors.initials: JM
authors.lastname: Arnold
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications*; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006943:Hyperglycemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D013311:Streptozocin / Q000633:toxicity
chemical_list: D002135:Calcium-Binding Proteins; D013311:Streptozocin; C033668:calpastatin; D002154:Calpain; C410233:Capns1 protein, mouse