ROLE OF GAQ SIGNALING IN CARDIAC MYOCYTE HYPERTROPHY & APOPTOSIS

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In hearts subjected to chronic overload, compensatory growth of the myocardium commonly transitions into decompensated congestive heart failure over time. Recently, myocyte dropout by apoptotic cell death has been implicated in the decreased contractile function seen in the decompensated heart. We have previously determined that moderate activation of signaling pathways downstream of G?q cause hypertrophy in cardiac myocytes whereas high-level activation of these pathways results in apoptosis. We hypothesize that hyperactivation of G?q-mediated signaling in the overloaded heart could result in apoptotic myocyte dropout and contribute to the decreased contractility seen in the decompensated heart. We propose to confirm our in vitro findings which suggest apoptosis as the mechanism for G?q-induced myocyte death by assessing the effects of high-level G?q activation on the subcellular structures of individual myocytes. Early markers of decreased contractile function and apoptotic cell death will be evaluated using electron microscopy including; disruption of myofilament organization, appearance of cytoplasmic vaculoes, and changes in nuclear and mitochondrial membrane structure.