PLoS ONE (Jan 2012)

Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model.

  • Cuiqing Liu,
  • Rajagopal Desikan,
  • Zhekang Ying,
  • Liubov Gushchina,
  • Thomas Kampfrath,
  • Jeffrey Deiuliis,
  • Aixia Wang,
  • Xiaohua Xu,
  • Jixin Zhong,
  • Xiaoquan Rao,
  • Qinghua Sun,
  • Andrei Maiseyeu,
  • Sampath Parthasarathy,
  • Sanjay Rajagopalan

DOI
https://doi.org/10.1371/journal.pone.0050767
Journal volume & issue
Vol. 7, no. 12
p. e50767

Abstract

Read online

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.