(Verbatim from the application): In the response-to-injury hypothesis of atherosclerosis, numerous factors are involved in atherosclerotic lesions resulting from local injury, including impairment of the arginine-NO pathway. NO and its precursor intermediate, N-hydroxyarginine (NOHA), are potent inhibitors of cell proliferation that interfere with the arginine-polyamine pathway. Deficient production of NOHA + NO may accelerate proliferation of vascular smooth muscle, macrophages and other cells. Arginase is a high turnover enzyme that utilizes arginine to form ornithine + urea. Ornithine is a precursor for polyamines required for cell growth. Elevated arginase activity causes increased conversion of arginine to polyamines at the expense of decreased conversion of arginine to NOHA + NO due to limiting arginine availability. Decreased production of NOHA + NO further amplifies polyamine production due to decreased negative feedback on the arginine-polyamine pathway. Increased arginase expression is characteristic of atherosclerotic lesions and administration of arginase inhibitors to animals with atherosclerosis decreases disease progression. The central hypothesis that drives this proposal is that atherosclerosis is associated with the induction of arginase, leading to increased polyamine production that is further enhanced by diminished production 01 NOHA + NO. The principal objective of the proposed research is to determine whether the increased cell proliferation in atherosclerosis is attributed to increased arginase activity and consequent increased polyamine production coupled to decreased NOHA and NO production. The rationale for this objective is based on our previous findings that NOHA and NO inhibit cell growth by interfering with two sequential steps in the arginine-polyamine pathway.
Two specific aims are proposed to address the objective: (a) to elucidate the mechanisms by which increased arginase activity leads to increased cell proliferation, and (b) to determine the effectiveness and mechanisms by which arginase inhibitors slow the progression of atherosclerosis in animal models of atherosclerosis. The feasibility of this approach is borne out by the extensive preliminary data that support the central hypothesis.
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