Effects of a Novel Pharmacologic Inhibitor of Myeloperoxidase in a Mouse Atherosclerosis Model

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.炎症与氧化应激在动脉粥样硬化（atherosclerosis）的发病机制中发挥核心作用。髓过氧化物酶（myeloperoxidase）已被广泛证实是动脉粥样硬化中炎症及氧化还原依赖过程的关键介导因子。然而，合成型髓过氧化物酶抑制剂对动脉粥样硬化的影响尚未得到充分研究。本研究将载脂蛋白E基因敲除（ApoE−/−）小鼠随机分为低剂量、高剂量INV-315组，予高脂饮食干预16周。结果显示，INV-315可降低斑块负荷，并改善乙酰胆碱诱导的内皮功能。上述作用未伴随不良事件，亦未引起体重或血压的异常变化。INV-315治疗可下调主动脉内诱导型一氧化氮合酶（iNOS）的基因表达，减少超氧阴离子生成与硝基酪氨酸含量。经INV-315处理后，循环中的白细胞介素-6（IL-6）及炎症性CD11b阳性/Ly6G低表达/7/4高表达单核细胞水平显著降低。急性预处理给予INV-315可阻断肿瘤坏死因子α（TNFα）介导的提睾肌静脉白细胞黏附反应，并抑制髓过氧化物酶活性。高剂量INV-315可通过体外胆固醇逆转运实验（ex-vivo reverse cholesterol transport assays），显著提升胆固醇外流（cholesterol efflux）能力。本研究结果提示，髓过氧化物酶抑制可能通过抑制氧化应激、增强胆固醇外流发挥抗动脉粥样硬化作用。上述发现证实了药物调控髓过氧化物酶在动脉粥样硬化中的作用。