Abstract 155: Antiatherosclerotic Effects of a Novel Pharmacologic Inhibitor of Myeloperoxidase in Atherosclerosis

Abstract

Objective: Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase (MPO) has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis including reverse cholesterol transport. In this study, we investigated safety and efficacy of a novel small molecule inhibitor of MPO (INV-315) in atherosclerosis. Methods and results: ApoE -/- mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine (26±4, 25±3 and 36±2% for atherosclerosis burden respectively and 42±7, 49±11 and 60.3±6% for maximal relaxation to acetylcholine in low, high dose and control groups respectively, p<0.05 for high-dose vs. placebo for both). These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a 2-3.5 fold decrease in iNOS gene expression, 1.9 fold decrease in superoxide production and 2-3.5 fold decrease in nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b + /Ly6G low /7/4 hi monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited MPO activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Conclusions: MPO inhibition may exert anti-atherosclerotic effects via inhibition of MPO-mediated oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of MPO in atherosclerosis.