Cardiac hypertrophy and heart failure are major causes of morbidity and mortality. Studies in cultured neonatal cardiomyocyte have implicated autocrine or paracrine stimulation of Gq and phospholipase C as mediators of myocardial hypertrophy. However, it has been difficult to establish the pathophysiologic roles of this putative hypertrophy signaling pathway in vivo. Toward that end, we employed cardiac specific overexpression of murine Galphaq in mice to intrinsically activate myocardial phospholipase C, and then evaluated cardiac mass, function, protein content, and gene expression. The Galphaq transgenic mice exhibit an unprecedented cardiac phenotype of hemodynamic load- independent hypertrophy, including the full range of hypertrophy- associated genes, with contractile dysfunction leading to overt heart failure in the face of acute volume challenge or chronic pressure overload. We will utilize this transgenic model of load-independent decompensating hypertrophy to: Identify the critical intracellular mediators of phospholipase C-stimulated hypertrophy by analyzing protein kinase C isoform, MAP kinase, p38, and Jun kinase activation, and through identifying genes with regulated expression in hypertrophy. (Specific Aim number 1); We will determine the role of decreased SERCA2 expression in the observed contractile dysfunction at the whole organ and isolated myocyte level and will attempt to correct the contractile defect in Galphaq mice by superimposed overexpression of SERCA2. (Specific Aim number 2); Determine the role of protein kinase Cepsilon activation in the cardiac hypertrophic response to Galphaq and pressure overload using transgenic mice overexpressing a dominant negative PKCepsilon (Specific Aim number 3). Our combined approach of evaluating the determinants of hypertrophy in whole hearts, isolated cells, and within the cell at the molecular level, all in a unique and novel transgenic model of load-independent decompensating cardiac hypertrophy is expected to greatly advance our understanding of the mechanisms of hypertrophy and heart failure development. In addition it is likely that new therapies, targeted toward specific signal transducers or effectors, will result from these studies.
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