verbatim): In response to various forms of heart disease the myocardium undergoes hypertrophic growth to compensate for a loss in cardiac output. While this response is initially beneficial, it eventually leads to pathology and heart failure. Despite years of investigation, the molecular pathways that result in cardiac hypertrophy remain largely unknown. The transcription factor GATA4 has been shown to play an important role in regulating the hypertrophic response at the transcriptional level (Herzig, et al., 1997; Hasegawa, et al., 1997). To investigate the molecular mechanisms whereby GATA4 regulates the hypertrophic response, a yeast 2-hybrid screen was performed which identified the transcription factor NF-AT3 (nuclear factor of activated T-cells). Studies in T-cells have demonstrated that NF-AT factors are sequestered in the cytoplasm until activated by the phosphatase calcineurin in response to stress or stimuli that increase intracellular calcium. Our recent results demonstrate that the myocardium also utilizes this stress-response signaling pathway. Transgenic mice expressing a constitutively active form of calcineurin or a constitutively nuclear NF-AT3 protein in the heart develop substantial hypertrophy resulting in heart failure. Furthermore, inhibition of endogenous calcineurin activity with the drug cyclosporin A prevents angiotensin II and adrenergic-mediated hypertrophy by effecting the transcription factor NF-AT3 and its ability to activate hypertrophic response genes. The goals of this study are: 1) To determine the extent to which calcineurin-mediated signaling is necessary for cardiac hypertrophy in multiple animal models using pharmacologic inhibitors. 2) To genetically inhibit calcineurin activity specifically in the hearts of transgenic mice. 3) To determine the down-stream consequences of calcineurin signaling in the myocardium and its effect on PKC and MAPK signaling pathways. Both transgenic and in vitro culture systems are proposed to elucidate a potentially novel cardiac response pathways. This novel pathways is predicted to regulate cardiac hypertrophy through any stimulus that increases intracellular calcium concentration (mechanical load, stretch, angiotensin II, etc.). The potential ramifications of the successful elucidation of this pathway are extensive given that cyclosporin A and FK506 are potent inhibitors of calcineurin.
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