Reversal of cardiac hypertrophy in transgenic disease models by calcineurin inhibition

Heart disease remains one of the leading causes of morbidity and mortality in the industrialized nations of the world. Intense investigation has cente red around identifying and manipulating intracellular signaling pathways th at direct hypertrophic and myopathic responses in an attempt to intervene i n the progression or reverse certain forms of heart disease. We show here t hat cyclosporin A-mediated inhibition of the calcium-regulated phosphatase, calcineurin (PP2B), reverses cardiac hypertrophy and myopathic dilation in two transgenic mouse models of cardiomyopathy. Reversal was demonstrated b y gravimetric analysis, echocardiography, histological analysis, and molecu lar analysis of hypertrophy-associated gene expression. In contrast, a thir d mouse model of hypertrophic cardiomyopathy due to activated NFAT3 cardiac -specific expression was not affected by cyclosporin A. These results sugge st that calcineurin may function in the long-term maintenance of cardiac hy pertrophy or myopathic disease slates.