The work proposed is based on the principal investigator?s previous studies in connection with this Program Project and recent preliminary data obtained related to the study of vascular function in mice. Significant differences in the regulation by endothelial mediators of skeletal muscle and coronary vessels between young and aged mice and endothelial nitric oxide synthase knockout (eNOS-KO) and control mice were found to allow us to formulate the hypothesis that the vascular dysfunction observed with aging is characterized by a progressive reduction in the synthesis or bioavailability of endothelium-derived NO resulting in or caused by a increased oxidant stress in endothelial cells. This age related vascular dysfunction may result in an enhanced incidence of cardiac myopathy or vascular and myocyte mecrosis and apoptosis, and a decrease in the maximal lifespan in mice lacking the ability to synthesize NO.
In Specific Aim 1 we plan to investigate the nature of the gender dependent differences in the function of coronary and skeletal muscle arteries and arterioles from eNOS-KO and control, wild type (WT) mice and to investigate the mechanisms (via prostaglandins or EDHF) of the altered mediation of vascular responses in the absence of endothelium-derived NO in young and aging animals.
In Specific Aim 2 we will characterize the aging vascular (endothelial) phenotype and use a variety of strategies to redress the balance between endothelial production of oxidants and NO to favorably affect NO?s biological activity in order to improve the age-associated vascular dysfunction in mice. Among these strategies are the administration of cAMP-enhancing agents, chronic treatment with statins or ACE inhibitors, exercise training and viral transfection of the eNOS gene. Pacing-induced decompensated heart failure in dogs and dilated cardiomyopathy in human patients is characterized by a reduction in endothelial NO synthesis and may be the initiating cause leading to cardiac dysfunction. Accordingly in Specific Aim 3 we plan to evaluate the effects of the restoration of NO production in the process of recovery of coronary vascular function after heart failure. For this purpose we will assess endothelial regulation of coronary arterioles of dogs after cessation of pacing and after treatment of the dogs with statins as well as coronary arterioles from the hearts of patients with left ventricular assist devices (LVAD). We believe that the proposed studies will lead to a better understanding of the causes of age-related vascular dysfunction and the process of cardiac decompensation and have the potential of achieving maintenance of endothelial control by NO and to arrest or even reverse the natural history of the development of these conditions.
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