Inhibition of Cardiac Hypertrophy by Modulation Calcineurin-dependent Signal Transduction

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Cardiac hypertrophy represents the heart s response to increased biomechanical stress such as arterial hypertension. While traditionally viewed as a compensatory mechanism, several clinical studies as well as animal models have shown that sustained cardiac hypertrophy is rather maladaptive, ultimately leading to heart failure and sudden death. The phosphatase calcineurin and its downstream target, the transcription factor NFAT, have been shown to play a critical role in the pathogenesis of cardiomyocyte hypertrophy. Constitutive activation of calcineurin in mouse hearts leads to massive cardiac enlargement and heart failure. Conversely, ablation of calcineurin in the heart renders mice resistant to hypertrophy. We have recently identified a novel family of muscle-specific proteins, termed calsarcins, that bind to calcineurin. Moreover, we generated calsarcin-deficient mice, which reveal a markedly exaggerated hypertrophic response to both pressure overload and chronic calcineurin activation. To examine calcineurin as a molecular target for antihypertrophic strategies we now propose to explore several complimentary experimental approaches: (1) Utilizing adenoviruses, we first aim to test if overexpression of calsarcin-1 or the novel novel calcineurin-/NFAT-inhibiting kinase, DYRK1A, are sufficient to inhibit cardiomyocyte hypertrophy in vitro. (2) We have generated a novel transgenic mouse model with cardiac overexpression of calsarcin-1 and plan to examine if calsarcin can inhibit hypertrophy in several experimental models, including pressure overload. (3) We will analyze if adeno-associated viruses encoding for calsarcin-1 are able to attenuate hypertrophy in vivo. (4) We plan to perform a cDNA library expression screen in muscle cell lines stably transfected with a NFAT reporter gene in order to identify additional cardiacspecific modulators/inhibitors of the calcineurin/NFAT-pathway. In summary, we expect to further unravel calcineurin-dependent signal-transduction in the heart as well as to identify novel molecular targets for the prevention and treatment of myocardial hypertrophy and failure.