1. Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes
- Author
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Li, Ying, Ma, Jian, Zhu, Huaqing, Singh, Manpreet, Hill, David, Greer, Peter A., Arnold, J. Malcolm, Abel, E. Dale, and Peng, Tianqing
- Subjects
Type 1 diabetes -- Risk factors -- Care and treatment -- Research ,Collagen -- Physiological aspects -- Research ,Heart cells -- Physiological aspects -- Research ,Hyperglycemia -- Risk factors -- Development and progression -- Research ,Health - 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., Cardiovascular complications are the leading cause of diabetes-related morbidity and mortality (1). Diabetes not only exacerbates cardiac injury after myocardial infarction or ischemia/reperfusion (2-4) but also directly damages the heart, [...]
- Published
- 2011
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