CALPASTATIN OVER-EXPRESSION REDUCES CARDIAC FIBROSIS IN A MURINE MODEL OF TYPE 2 DIABETES

Cardiovascular complications are the leading cause of diabetes-related morbidity and mortality. Calpain, a calcium-dependent protease, is increased in diabetic hearts yet its role in diabetic heart disease has not been demonstrated. We hypothesized that inhibition of calpain activity via calpastatin (CAST) over-expression will reduce the onset of myocardial fibrosis, a hallmark of diabetic cardiomyopathy, in the Type 2 murine model, db/db. Histological analysis together with gene expression measurements showed calpastatin over-expression reduced collagen content in db/db-CAST hearts. In order to understand the mechanisms responsible for this change, fibroblasts and known mediators of collagen synthesis and degradation were studied. Results indicated that calpain-induced derangements in MMP activity, stimulation of immune cells and up- regulation of cytokines responsible for promoting fibroblast differentiation and proliferation were reversed by calpastatin over-expression. This study shows that calpain inhibition is an effective means of decreasing collagen accumulation in the diabetic heart