Myeloperoxidase inhibition in mice alters atherosclerotic lesion composition

Abstract

Myeloperoxidase (MPO) is a highly abundant protein within the neutrophil that is associated with lipoprotein oxidation, and increased plasma MPO levels are correlated with poor prognosis after myocardial infarct. Thus, MPO inhibitors have been developed for the treatment of heart failure and acute coronary syndrome in humans. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide PF-06282999 is a recently described selective small molecule mechanism-based inactivator of MPO. Here, utilizing PF-06282999, we investigated the role of MPO to regulate atherosclerotic lesion formation and composition in the Ldlr-/- mouse model of atherosclerosis. Though MPO inhibition did not affect lesion area in Ldlr-/- mice fed a Western diet, reduced necrotic core area was observed in aortic root sections after MPO inhibitor treatment. MPO inhibition did not alter macrophage content in and leukocyte homing to atherosclerotic plaques. To assess non-invasive monitoring of plaque inflammation, [18F]-Fluoro-deoxy-glucose (FDG) was administered to Ldlr-/- mice with established atherosclerosis that had been treated with clinically relevant doses of PF-06282999, and reduced FDG signal was observed in animals treated with a dose of PF-06282999 that corresponded with reduced necrotic core area. These data suggest that MPO inhibition does not alter atherosclerotic plaque area or leukocyte homing, but rather alters the inflammatory tone of atherosclerotic lesions; thus, MPO inhibition could have utility to promote atherosclerotic lesion stabilization and prevent atherosclerotic plaque rupture.

Therapeutic targeting of neutrophil exocytosis

“…MPO mediates endothelial damage and is present in atherosclerotic lesions . MPO inhibition alters inflammation within atherosclerotic lesions and helps prevent atherosclerotic plaque rupture in murine models . The association of multiple granule cargoes with atherosclerotic lesions supports the concept that interfering with neutrophil exocytosis rather than inhibition of selective secretory proteins is more likely to produce positive outcomes.…”

NETosis as a Pathogenic Factor for Heart Failure

“…In addition, Cl-amidine treatment delays carotid artery thrombosis in a photochemical injury model [ 253 ]. However, although the MPO inhibitor PF-06282999 cannot change the macrophage content and white blood cell homing in atherosclerotic plaques, it can reduce the necrotic core area, suggesting that PF-06282999 promotes the stability of atherosclerotic lesions in the LDLR −/− mouse model of atherosclerosis [ 254 ]. Likewise, another MPO inhibitor INV-315 results in reduced plaque burden and enhanced cholesterol efflux, decreased aortic iNOS gene expression, superoxide production, and nitrotyrosine content, and improved endothelial function of acetylcholine [ 255 ].…”

Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases

“…GKT137831 also rescued cardiac function after I/R injury in mice [ 162 ]. In mice model of atherosclerosis, MPO inhibitors were able to alter the atherosclerotic lesion composition and cardiac remodeling [ 163 ].…”