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.
Highlights
Atherosclerosis is a chronic inflammatory disease that is hallmarked by hyperlipidemiainduced vascular inflammation and inflammatory cell recruitment to the vessel wall [1,2,3,4]
MPO activity is reduced yet lesion area is unaltered in low density lipoprotein receptor (Ldlr)-/- mice treated with MPO inhibitor PF-06282999
Plasma MPO activity was assessed; at the 15 mg/kg dose, MPO activity and total MPO levels were reduced by 85% and 44%, respectively (Fig 1A and 1B), which equated to an 73% reduction in MPO activity when normalized to MPO levels (Fig 1C)
Summary
Atherosclerosis is a chronic inflammatory disease that is hallmarked by hyperlipidemiainduced vascular inflammation and inflammatory cell recruitment to the vessel wall [1,2,3,4]. Though statins are a mainstay of treatment to reduce LDL and prevent.
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