Molecular Pathogenesis of Cardiac Failure due to Gene Abnormalities

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Idiopathic cardiomyopathy was defined as cardiomyopathy of unknown etiology. Recent molecular genetic analysis has revealed that gene abnormalities are involved in the etiology and/or pathogenesis of idiopathic cardiomyopathy. As well, hypertensive cardiomyopathy may also be relevant to the gene abnormalities in the pathogenesis. In this study, we have revealed that mutations in the genes for Z-disk elements, TTN, TCAP, MLP, and Cypher, cause cardiomyopathy. Functional studies of the mutations in each disease gene have shown that hypertrophic cardiomyopathy-related mutations increase the binding ability of the Z-disk elements, whereas dilated cardiomyopathy-related mutations decrease the binding ability. It also has been demonstrated that the Z-disk plays a key role in the stretch-sensing of cardiomyocytes from the analysis of a well known dilated cardiomyopathy model of MLP deficient mice. It was suggested that the stretch-response involved phosphorylation of Z-disk proteins, because the Z-disk protein abnormalities were predicted to change the distribution of calcineurin and PKC. In addition, Ca-sensitization and -desensitization played a crucial role in the pathogenesis of cardiac hypertrophy and failure, respectively. Analysis of hypertrophied and dilated hearts from M21-transgenic mice and Dah1 salt-sensitive hypertensive rats by DNA-chip technology showed that a number of genes were involved in the pathogenesis of cardiomyopathy. One of the new genes identified to be differentially expressed in the cardiac hypertrophy and failure is a growth factor-like gene specifically expressed in the heart. We identified a mutation in that growth factor-like gene that was associated with hypertensive cardiomyopathy.