TY - JOUR
T1 - Effects of a Novel Pharmacologic Inhibitor of Myeloperoxidase in a Mouse Atherosclerosis Model
AU - Liu, Cuiqing
AU - Desikan, Rajagopal
AU - Ying, Zhekang
AU - Gushchina, Liubov
AU - Kampfrath, Thomas
AU - Deiuliis, Jeffrey
AU - Wang, Aixia
AU - Xu, Xiaohua
AU - Zhong, Jixin
AU - Rao, Xiaoquan
AU - Sun, Qinghua
AU - Maiseyeu, Andrei
AU - Parthasarathy, Sampath
AU - Rajagopalan, Sanjay
N1 - Funding Information:
The authors would like to acknowledge that this work was made possible via a collaborative effort between InVasc Therapeutics and Ohio State University. InVasc Therapeutics is a non-publicly traded private company based in Columbus, OH. Dr. Rajagopal Desiakan, one of the co-authors, was fully employed by InVasc Therapeutics at the time of this work. Cuiqing Liu was a co-founder of the company along with Sampath Parthasarathy and have patents on INV315 and related myeloperoxidase inhibitors that are currently pending approval at the US Patent and Trade office. The molecules that were investigated in this work were licensed for use by InVasc Therapeutics. Funding for this work was through a National Institutes of Health SBIR grant (R43HL103269) awarded to InVasc Therapeutics with OSU as a subcontractor. Neither Dr. Parthasarathy nor Cuiqing Liu are employees of InVasc but do function in an advisory role to the company. The authors declare that the relationship with InVasc does not alter their adherence to all of the PLOS ONE policies on sharing data and materials.
PY - 2012/12/10
Y1 - 2012/12/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84870887288
U2 - 10.1371/journal.pone.0050767
DO - 10.1371/journal.pone.0050767
M3 - Article
C2 - 23251382
AN - SCOPUS:84870887288
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e50767
ER -