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:10.1371/journal.pone.0050767

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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	e50767
Journal	PloS one
Volume	7
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0050767
State	Published - Dec 10 2012
Externally published	Yes

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@article{ee7675d74a934726968053bb4551315e,

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+/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.",

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

note = "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. ",

year = "2012",

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doi = "10.1371/journal.pone.0050767",

language = "English (US)",

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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.

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

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