TARGETED OVEREXPRESSION OF PROTEIN-KINASE-C BETA-2 ISOFORM IN MYOCARDIUM CAUSES CARDIOMYOPATHY

Increased cardiovascular mortality occurs in diabetic patients with or without coronary artery disease and is attributed to the presence of diabetic cardiomyopathy, One potential mechanism is hyperglycemia that has been reported to activate protein kinase C (PKC), preferentially the beta isoform, which has been associated with the development of mi cro-and macrovascular pathologies in diabetes mellitus, To establish t hat tile activation of the PKC beta isoform can cause cardiac dysfunct ions, we have established lines of transgenic mice with the specific o verexpression of PKC beta 2 isoform in the myocardium. These mice over expressed the PKC beta 2 isoform transgene by 2- to 10-fold as measure d by mRNA, and proteins exhibited left ventricular hypertrophy, cardia c myocyte necrosis, multifocal fibrosis, and decreased left ventricula r performance without vascular lesions, The severity of the phenotypes exhibited gene dose-dependence, Up-regulation of mRNAs for fetal type myosin heavy chain, atrial natriuretic factor, c-fos, transforming gr owth factor, and collagens was also observed, Moreover, treatment with a PKC beta-specific inhibitor resulted in functional and histological improvement, These findings have firmly established that the activati on of the PKC beta 2 isoform can cause specific cardiac cellular and f unctional changes leading to cardiomyopathy of diabetic or nondiabetic etiology.