title: Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.
abstract: 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(+)/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 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.
authors.affiliation: Department of Physiology, Hangzhou Normal University, Hangzhou, China.
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Liu
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Desikan
authors.forename: Zhekang
authors.initials: Z
authors.lastname: Ying
authors.forename: Liubov
authors.initials: L
authors.lastname: Gushchina
authors.forename: Thomas
authors.initials: T
authors.lastname: Kampfrath
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deiuliis
authors.forename: Aixia
authors.initials: A
authors.lastname: Wang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xu
authors.forename: Jixin
authors.initials: J
authors.lastname: Zhong
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Rao
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Andrei
authors.initials: A
authors.lastname: Maiseyeu
authors.forename: Sampath
authors.initials: S
authors.lastname: Parthasarathy
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D009195:Peroxidase