Signaling for cardioprotection against oxidative stress

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DESCRIPTION (provided by applicant): The heart has endogenous protective mechanisms against oxidative stress-induced damage. The cellular mechanisms that lead to the prevention and protection of myocardial damage, however, have not been defined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat heart disease. My long-range goal is to identify the signal transduction mechanisms, leading to the protection of adult cardiac myocytes. The objective of this application is to evaluate specifically the role of GATA-4 in cell survival signaling induced by hepatocyte growth factor and endothelin-l. The central hypothesis of the application is that hepatocyte growth factor and endothelin-1 protect cardiac myocytes against oxidative stress-induced cell death, in part, by upregulating cell survival genes via the activation of GATA-4. The hypothesis has been formulated on the basis of strong preliminary data, which suggest that hepatocyte growth factor and endothelin-1 protect cardiac myocytes against oxidative stress and activate GATA-4. The rationale for the proposed research is that, once knowledge of the mechanisms that are responsible for the protection of cardiac myocytes has been obtained, it will lead to new strategies that can be used to prevent and/or treat heart disease, thereby reducing the morbidity and mortality that are associated with this condition. I am uniquely prepared to undertake the proposed research because my laboratory has demonstrated that hepatocyte growth factor and endothelin-1 protect adult cardiac myocytes against oxidative stress and also phosphorylate GATA-4, thus many of the techniques and reagents are already available. The central hypothesis will be tested and the objective of the application accomplished by pursuing two specific aims: 1) Determine the mechanism of GATA-4 activation, and 2) Determine the common mechanism by which hepatocyte growth factor and endothelin-1 protect cardiac myocytes. The proposed work is innovative, because it will combine cellular and animal models of adult cardiac myocytes. It is my expectation that GATA-4 plays an important role in signal transduction for cardiac myocyte protection. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions for heart disease. In addition, it is expected that the results will fundamentally advance the field of cardiac muscle cell biology.