Atherosclerosis in animals and humans is characterized by an unresponsiveness of arteries and arterioles to endothelium-dependent vasodilators. Recent studies indicate that high cholesterol and/or LDL could play a significant role in inducing such alteration by reducing the synthesis of the endothelial-derived relaxing factor; nitric oxide (NO). AS reduction in the production of NO by the vessel wall could promote smooth muscle cell proliferation in the intima and platelet aggregation, adhesion, and degranulation, which appear to be important events in atherosclerosis and vascular pathologies. However, the precise mechanism by which NO synthesis is impaired by high cholesterol has not been defined. Substantial evidence support the notion that high cholesterol and/or LDL levels affect a step involving the transport of L-arginine, the precursor of NO in endothelial cells. Indeed, preliminary evidence obtained by the applicant indicates that high cholesterol significantly reduces L-arginine transport in these cells. However, evidence is lacking concerning the status of l-arginine transport in hypercholesterolemic states. The proposed research plan will focus on L-arginine transport in vascular endothelial cells to determine its role in the dysfunction induced by high cholesterol (LDL) states.
The specific aims are; 1) To provide a detailed characterization of L- arginine transport in vascular endothelial cells. This section will include studies to define the kinetic behavior of L-[3H]arginine transport, membrane potential dependence, the effect of external pH changes, and competition studies to determine the selectivity of the transport mechanism. 2) To evaluate the effect of cholesterol and LDL/oxidized LDL on arginine transport in basal and stimulated conditions and 3), to identify possible sites of action of these agents by determining the pathway(s) regulating arginine transport under normal and altered conditions (high cholesterol/LDL). For this purpose, the role of the receptor-mediated calcium mobilization (G-proteins; InsP3/Ca2+; DAG/PkC, Ca2+/calmodulin, etc.) in the regulation of arginine transport will be determined using pharmacological agents that selectively inhibit the different steps of the phosphoinositol cascade, Ca2+/calmodulin-dependent processes, etc. Similar experiments will be conducted measuring NO release to assess the coupling between arginine transport and NO synthesis. The role of membrane potential changes as a link between the activation of NO synthesis and L-arginine transport will be evaluated. The proposed research program will contribute to our basic understanding of the cellular mechanisms underlying normal and altered amino acid transport in relationship to endothelial dysfunction int he pathogenesis of atherosclerosis, hypertension and congestive heart failure.
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