The broad long-term objective of this research proposal is to establish arginase I as a novel regulator of vascular function. We have discovered that vascular smooth muscle cells (SMC) express arginase I and that vascular mitogens and atherogenic factors found at sites of vascular injury stimulate arginase I gene expression. The central hypothesis of this proposal is that arginase I is a critical regulator of the SMC response to vascular injury. To test our hypothesis, we plan to pursue the following 3 complementary and linked specific aims.
In aim 1, the effect of arginase on vascular SMC proliferation, migration, collagen and nitric oxide (NO) synthesis will be investigated. If arginase I stimulates SMC growth, migration, or collagen synthesis we will determine whether polyamines or L-proline mediate these actions. In addition, the effect of arginase I on cell cycle proteins will be explored. In contrast, if arginase I inhibits inflammatory cytokine-mediated NO production we will examine if this is mediated via the depletion of intracellular L-arginine. We will also determine if the inhibition of NO formation by arginase I prevents SMC apoptosis.
In aim 2, the regulation and role of arginase I on the response to arterial injury will be investigated. These studies will examine the expression of arginase I as well as the production of polyamines, L-proline, and NO using the rat carotid artery injury model. We will also determine whether inhibition of arginase I activity using pharmacological and antisense approaches attenuates the remodeling response following arterial injury. Alternatively, we will examine whether arginase I gene transfer to the vessel wall exacerbates the remodeling response. In addition, we will generate mice with homozygous arginase I inactivation targeted specifically to vascular SMC and determine whether this influences the remodeling response.
In aim 3, the regulation and role of arginase I in hyperhomocysteinemia will be investigated using cultured SMC and genetic and dietary animal models of hyperhomocysteinemia. It is anticipated that this project will (a) establish arginase I as a novel regulator of the vessel wall's response to injury and (b) implicate the arginase I enzyme as a promising new therapeutic target in treating atheroproliferative disorders of the vessel wall.
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