Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.
Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.
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DOI：
10.1371/journal.pone.0050767
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rajagopalan S
中科院分区：
文献类型：
--
作者：
Liu C;Desikan R;Ying Z;Gushchina L;Kampfrath T;Deiuliis J;Wang A;Xu X;Zhong J;Rao X;Sun Q;Maiseyeu A;Parthasarathy S;Rajagopalan S
Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis. However, the effect of synthetic myeloperoxidase inhibitors on atherosclerosis has been insufficiently studied. In this study, 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. These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a decrease in iNOS gene expression, superoxide production and nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b+/Ly6Glow/7/4hi 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 myeloperoxidase activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Our results suggest that myeloperoxidase inhibition may exert anti-atherosclerotic effects via inhibition of oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of myeloperoxidase in atherosclerosis.
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