Journal article
Targeted Inhibition of Calpain Reduces Myocardial Hypertrophy and Fibrosis in Mouse Models of Type 1 Diabetes
Diabetes (New York, N.Y.), Vol.60(11), pp.2985-2994
11/2011
DOI: 10.2337/db10-1333
PMCID: PMC3198063
PMID: 21911754
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. RESEARCH DESIGN AND 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.
Details
- Title: Subtitle
- Targeted Inhibition of Calpain Reduces Myocardial Hypertrophy and Fibrosis in Mouse Models of Type 1 Diabetes
- Creators
- Ying Li - Western UniversityJian Ma - Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, CanadaHuaqing Zhu - Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, CanadaManpreet Singh - Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, CanadaDavid Hill - Department of Medicine, University of Western Ontario, London, Ontario, CanadaPeter A Greer - Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario, CanadaJ. Malcolm Arnold - Department of Medicine, University of Western Ontario, London, Ontario, CanadaE. Dale Abel - Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine, University of Utah, Salt Lake City, UtahTianqing Peng - Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.60(11), pp.2985-2994
- Publisher
- American Diabetes Association
- DOI
- 10.2337/db10-1333
- PMID
- 21911754
- PMCID
- PMC3198063
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 11/2011
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025295902771
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