ARRA: Oxidative Stress and Myocardial Function

Project Summary for "Oxidative Stress and Myocardial Function' It is well established that cardiac contractile reserve declines while the incidence of heart failure increases dramatically with age. According to the "free radical theory of aging," cardiac dysfunction may be the result of oxidative stress-induced myocardial remodeling. Our long-term goal is to elucidate signal transduction and cellular and molecular mechanisms by which post-translational modifications of myofilament proteins, lead to alterations in cardiac muscle function and ultimately to heart failure. The hypothesis underlying this work is that oxidative stress-induced modifications of cardiac contractile proteins are exacerbated with age and cardiac disease progression, and lead to impaired myofilament function. To test this hypothesis we propose a comprehensive and versatile set of experiments using a mixture of mechano-energetic and biochemical/biophysical approaches. The proposed research will utilize the spontaneously hypertensive rat model, regarded for years as a good model for human systemic hypertension, recently demonstrated as an excellent model to study oxidative stress-associated contractile dysfunction. Our aims seek to: 1) Elucidate the oxidative stress-induced modifications of myofilament proteins in young, adult and old spontaneously hypertensive rats, compared with age matched normotensive Wistar-Kyoto rats. Experiments proposed here test the hypothesis that oxidative stress induces detectable modifications of myofilament proteins, and that aging and hemodynamic stress (hypertension) lead to distinctive levels of modifications, which may differentially modulate myofilament function. 2) Investigate the functional effects of oxidative stress with age and heart disease progression in WKY and SHR myocardium. Experiments proposed here test the hypothesis that oxidative stress-induced modifications of sarcomeric proteins alter myofilament activation and might be key determinants of cardiac dysfunction. Functional significance of oxidative stress-induced modifications will be evaluated in skinned papillary muscle fiber bundles and intact myocytes from SHR and WKY animals. Overall, these experiments will result in a better understanding of the timing and the hierarchy of cellular events leading to cardiac dysfunction during the normal myocardial senescence, and during the development of heart failure in the rat. This research could prove of paramount importance in unraveling mechanisms leading to heart failure and identifying new targets or target areas for rational drug design.