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

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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.

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Most cited references 21

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Myeloperoxidase, a leukocyte-derived vascular NO oxidase.

Stephan Baldus, Aldons J Lusis, Wenxin Ma … (2002)

Myeloperoxidase (MPO) is an abundant mammalian phagocyte hemoprotein thought to primarily mediate host defense reactions. Although its microbicidal functions are well established in vitro, humans deficient in MPO are not at unusual risk of infection. MPO was observed herein to modulate the vascular signaling and vasodilatory functions of nitric oxide (NO) during acute inflammation. After leukocyte degranulation, MPO localized in and around vascular endothelial cells in a rodent model of acute endotoxemia and impaired endothelium-dependent relaxant responses, to which MPO-deficient mice were resistant. Altered vascular responsiveness was due to catalytic consumption of NO by substrate radicals generated by MPO. Thus MPO can directly modulate vascular inflammatory responses by regulating NO bioavailability.

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Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways.

Sanjay Rajagopalan, Nitin P. Padture, Thomas Kampfrath … (2011)

Chronic exposure to ambient air-borne particulate matter of < 2.5 μm (PM₂.₅) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. To investigate the molecular mechanisms by which PM₂.₅ mediates inflammatory responses in a mouse model of chronic exposure. Here, we show that chronic exposure to ambient PM₂.₅ promotes Ly6C(high) inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91(phox)) deficiency prevented monocyte NADPH oxidase activation in response to PM₂.₅ and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47(phox) phosphorylation in TLR4 deficient animals. PM₂.₅ exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow-derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM₂.₅ exposure, whereas TLR4 deficiency attenuated this response. Taken together, our findings suggest that PM₂.₅ triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase-dependent mechanisms.

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Effect of early particulate air pollution exposure on obesity in mice: role of p47phox.

L. Chen, Sanjay Rajagopalan, Mianhua Zhong … (2010)

To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, <2.5 μm [PM(2.5)]) pollution on metabolic parameters, inflammation, and adiposity; and to investigate the involvement of oxidative stress pathways in the development of metabolic abnormalities. PM(2.5) inhalation exposure (6 h/d, 5 d/wk) was performed in C57BL/6 mice (wild type) and mice deficient in the cytosolic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47(phox) (p47(phox-/-)) beginning at the age of 3 weeks for a duration of 10 weeks. Both groups were simultaneously fed a normal diet or a high-fat diet for 10 weeks. PM(2.5)-exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM(2.5) or FA for 10 weeks. Consistent with insulin resistance, these abnormalities included enlarged subcutaneous and visceral fat contents, increased macrophage infiltration in visceral adipose tissue, and vascular dysfunction. Ex vivo-labeled and infused monocytes demonstrated increased adherence in the microcirculation of normal diet- or high-fat diet-fed PM(2.5)-exposed mice. p47(phox-/-) mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM(2.5). Early-life exposure to high levels of PM(2.5) is a risk factor for subsequent development of insulin resistance, adiposity, and inflammation. Reactive oxygen species generation by NADPH oxidase appears to mediate this risk.

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Author and article information

Contributors

Harald H. H. W. Schmidt: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 10 December 2012

Volume: 7

Issue: 12

Electronic Location Identifier: e50767

Affiliations

[1 ]Department of Physiology, Hangzhou Normal University, Hangzhou, China

[2 ]Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America

[3 ]InVasc Therapeutics, Tucker, Georgia, United States of America

Maastricht University, The Netherlands

Author notes

* E-mail: sanjay.rajagopalan@ 123456osumc.edu

Competing Interests: 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.

Conceived and designed the experiments: CL ZY SP SR. Performed the experiments: CL ZY LG TK JD AW XX AM. Analyzed the data: JZ XR. Contributed reagents/materials/analysis tools: RD. Wrote the paper: CL QS SR.

Article

Publisher ID: PONE-D-12-22660

DOI: 10.1371/journal.pone.0050767

PMC ID: 3519467

PubMed ID: 23251382

SO-VID: 436a8de5-0000-403e-a2e0-b7c70aad3a81

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 27 July 2012

Date accepted : 24 October 2012

Page count

Pages: 10

Funding

This study is partially supported by National Institutes of Health (NIH) grants R01ES017290 and R21 DK088522 (SR) R01AT004106 (SP) and NIH SBIR (R43HL103269-01) to InVasc Therapeutics (subcontract to OSU). Dr. Maiseyeu and Dr. Ying are supported by American Heart Association Great Rivers Affiliate Postdoctoral Fellowship Program (10POST4150090, 11POST7640030); Dr. Deiuliis is supported by NRSA grant (F32-DK083903). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

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Most cited references 21

Myeloperoxidase, a leukocyte-derived vascular NO oxidase.

Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways.

Effect of early particulate air pollution exposure on obesity in mice: role of p47phox.

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