Development of strategies for handling heart failure based on the molecular pathogenesis of cardiomyopathy

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Identification of novel disease genes for cardiomyopathy and functional analyses of various cardiomyopathy-associated mutations were performed. We identified novel disease genes for cardiomyopathy, such that CARP mutations in hypertrophic cardiomyopathy, nebulette mutations and BAG3 in dilated cardiomyopathy,and myopalladin mutations in hypertrophic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. Functional studies of the cardiomyopathy-associated mutations revealed that CARP mutations increased binding to titin and enhance the nuclear translocation. Nebulette mutations impaired sarcomerogenesis and BAG3 mutations increased susceptibility to stress-induced apoptosis. Myopalladin mutations impaired sarcomerogenesis. In addition, we revealed a molecular mechanism for calcium sensitivity of cardiac contraction by heart-specific small subunit of myosin phosphatase, M21.Moreover, it was demonstrated that a chemical enhancing calcium sensitivity of muscle contraction, SCH00013, could prolong the survival prognosis of dilated cardiomyopathy in lamina/C mutation knock-in mice, suggesting that the regulation of calcium sensitivity is a novel therapeutic/preventive strategy for heart failure associated with cardiomyopathy