AGING AND VENTRICULAR DYSFUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The "free radical theory of aging" first postulated in 1956 has been perhaps the most widely accepted theory for biology of aging. Aging-related accumulation of free radicals or oxidative stress has been demonstrated to be responsible for senescent organ damage and lifespan. This theory has paved its way to the modern concept of "mitochondrial theory of aging", which credits mitochondria as the main culprits for oxidative stress. Oxidant balance and mitochondrial function play crucial roles in the maintenance of normal cardiac contractile performance. Nevertheless, the precise mechanisms of action of oxidative stress and mitochondrial function in cardiac aging remain elusive. Evidence from our laboratory indicated that antioxidants metallothionein and catalase exert protective effects against aging-induced cardiac damage and prolong lifespan. Our lab has shown cardiac-specific expression of insulin-like growth I (IGF-1) improved cardiac contractile function in advanced age without compromising lifespan. Therefore, our central hypothesis is that oxidative stress with advanced age is the ultimate cause of enhanced apoptosis and ventricular dysfunction through a mechanism of reduced Akt phosphorylation, lessened Akt-dependent inactivation of Forkhead transcription factor and FasL-mediated apoptosis. Cardiomyocyte and echocardiographic function, heart morphology, cardiac excitation-contraction coupling, cardiac contractile protein expression, oxidative damage, mitochondrial function, DNA damage and apoptosis will be evaluated in transgenic mouse models with cardiac specific over-expression of antioxidants metallothionein, superoxide dismutase and IGF-1 in young, middle and old ages. Oxidative stress inducer paraquat and BSO will be used to examine if oxidative stress induction mimics cardiac aging.