ContextMyeloperoxidase (MPO), a leukocyte enzyme that promotes oxidation of
lipoproteins in atheroma, has been proposed as a possible mediator of atherosclerosis.ObjectiveTo determine the association between MPO levels and prevalence of coronary
artery disease (CAD).Design, Setting, and PatientsCase-control study conducted from July to September 2000 in a US tertiary
care referral center, including 158 patients with established CAD (cases)
and 175 patients without angiographically significant CAD (controls).Main Outcome MeasuresAssociation of MPO levels per milligram of neutrophil protein (leukocyte-MPO)
and MPO levels per milliliter of blood (blood-MPO) with CAD risk.ResultsLeukocyte- and blood-MPO levels were both significantly greater in patients
with CAD than in controls (P<.001). In multivariable
models adjusting for traditional cardiovascular risk factors, Framingham risk
score, and white blood cell counts, MPO levels were significantly associated
with presence of CAD, with an OR of 11.9 (95% CI, 5.5-25.5) for the highest
vs lowest quartiles of leukocyte-MPO and an OR of 20.4 (95% CI, 8.9-47.2)
for the highest vs lowest quartiles of blood-MPO.ConclusionsElevated levels of leukocyte- and blood-MPO are associated with the
presence of CAD. These findings support a potential role for MPO as an inflammatory
marker in CAD and may have implications for atherosclerosis diagnosis and
risk assessment.

https://jamanetwork.com/journals/jama/articlepdf/194339/JPC10032.pdf

Association between myeloperoxidase levels and risk of coronary artery disease.

Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of a number of reactive oxidant species. In addition to being an integral component of the innate immune response, evidence has emerged that MPO-derived oxidants contribute to tissue damage during inflammation. MPO-catalyzed reactions have been attributed to potentially proatherogenic biological activities throughout the evolution of cardiovascular disease, including during initiation, propagation, and acute complication phases of the atherosclerotic process. As a result, MPO and its downstream inflammatory pathways represent attractive targets for both prognostication and therapeutic intervention in the prophylaxis of atherosclerotic cardiovascular disease.

Myeloperoxidase and Cardiovascular Disease

In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine (NO2Tyr) and myeloperoxidase (MPO), a protein that catalyzes generation of nitrating oxidants, serve as independent predictors of atherosclerotic risk, burden, and incident cardiac events. We now show both that apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is a selective target for MPO-catalyzed nitration and chlorination in vivo and that MPO-catalyzed oxidation of HDL and apoA-I results in selective inhibition in ABCA1-dependent cholesterol efflux from macrophages. Dramatic selective enrichment in NO2Tyr and chlorotyrosine (ClTyr) content within apoA-I recovered from serum and human atherosclerotic lesions is noted, and analysis of serum from sequential subjects demonstrates that the NO2Tyr and ClTyr contents of apoA-I are markedly higher in individuals with cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher NO2Tyr and ClTyr contents of the lipoprotein are each significantly associated with diminished ABCA1-dependent cholesterol efflux capacity of the lipoprotein. MPO as a likely mechanism for oxidative modification of apoA-I in vivo is apparently facilitated by MPO binding to apoA-I, as revealed by cross-immunoprecipitation studies in plasma, recovery of MPO within HDL-like particles isolated from human atheroma, and identification of a probable contact site between the apoA-I moiety of HDL and MPO. To our knowledge, the present results provide the first direct evidence for apoA-I as a selective target for MPO-catalyzed oxidative modification in human atheroma. They also suggest a potential mechanism for MPO-dependent generation of a proatherogenic dysfunctional form of HDL in vivo.

/pdf/apolipoprotein-a-i-is-a-selective-target-for-myeloperoxidase-3z921a9d08.pdf

Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease

Reactive oxygen species in cardiovascular disease.

A marked increase in interest has occurred over the last few years in the role that mammalian heme peroxidase enzymes, primarily myeloperoxidase, eosinophil peroxidase, and lactoperoxidase, may play in both disease prevention and human pathologies. This increased interest has been sparked by developments in our understanding of polymorphisms that control the levels of these enzymes, a greater understanding of the basic chemistry and biochemistry of the oxidants formed by these species, the development of specific biomarkers that can be used in vivo to detect damage induced by these oxidants, the detection of active forms of these peroxidases at most, if not all, sites of inflammation, and a correlation between the levels of these enzymes and a number of major human pathologies. This article reviews recent developments in our understanding of the enzymology, chemistry, biochemistry and biologic roles of mammalian peroxidases and the oxidants that they generate, the potential role of these oxidants in human disease, and the use of the levels of these enzymes in disease prognosis.

Caroline Fournier

Papers

A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians