Aldosterone is implicated in the process of myocardial remodeling and failure . Aldosterone may affect myocardial phenotype by regulating inflammation, myocyte contraction and relaxation, oxidative stress, and the interstitial matrix through a variety of mechanisms. In in vitro studies, aldosterone induces myocyte apoptosis, p67 phox and pro-inflammatory signal mediators such as NOS2. These observations lead us to the hypothesis that aldosterone mediates the phenotypic responses of myocardial cells in hemodynamic overload and increased aldosterone system stimulation . Peroxisome proliferator-activated receptor (PPAR) signaling , although regulators of energy control, attenuate cardiac hypertrophy, oxidative stress and apoptosis and may improve myocardial remodeling through pathways such as inflammation . We will explore these pathways by manipulating aldosterone levels, in vivo in mice and in vitro in cardiac myocytes and fibroblasts and their interaction with PPARs in mediating structural and functional remodeling at the molecular, cellular and organ levels.
In Aim 1 we will test the role of aldosterone and PPARs in mediating pressure overload cardiac remodeling . We will test the hypothesis that PPARs inhibit aldosterone-induced adverse cardiac remodeling. We will use mice with pressure overload and chroni c aldosterone infusions . We will use synthetic PPAR activators, fenofibrate and troglitazone, to determine if cardiac remodeling is inhibite d and further test if aldosterone mediates remodeling via progression of chronic inflammation or oxidative stress in the myocardium of PPARalpha null mice.
In Aim 2 we will test the role of aldosterone in inducing a hypertrophic/proliferative and apoptotic phenotype in myocardial remodeling . In in vivo experiments, we will test the mechanism whereby aldosterone induces a myocardial phenotype via a) the EGFR and MAPK pathway;and b) oxidative stress.
In Aim 3 we will test the role of aldosterone in mediating an abnormal myocyte contractile phenotype. We will test the hypothesis that aldosterone exerts both acute and chronic effects on myocyte contractile phenotype. Myocyte contraction/relaxation and intracellular calcium transients will be measured simultaneously in adult rat and mouse myocytes following short (min ) or long (hrs) term exposure to exogenous aldosterone in vitro. These studies will provide new understanding of the mechanisms of aldosterone signaling in the pressure overload heart and will have direct relevance to a common cause of heart failure in patients.
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