Serum Myeloperoxidase Levels Are Associated With the Future Risk of Coronary Artery Disease in Apparently Healthy Individuals

Meuwese, Marijn C.; Stroes, Erik S.G.; Hazen, Stanley L.; Miert, Joram N. van; Kuivenhoven, Jan Albert; Schaub, Robert G.; Wareham, Nicholas J.; Luben, Robert; Kastelein, John J.P.; Khaw, Kay Tee; Boekholdt, S. Matthijs

doi:10.1016/j.jacc.2007.03.033

Cited by 390 publications

(264 citation statements)

References 29 publications

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“…MPO levels have been shown in multiple studies to track with incident risks of CVD events in subjects (53,(55)(56)(57). The present studies may help to explain prior reports of pro-inflammatory HDL in the acute phase setting, as well as during chronic inflammation such as in CVD.…”

Section: Discussionsupporting

confidence: 60%

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

Undurti

Huang

Lupica

et al. 2009

Journal of Biological Chemistry

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238

178

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High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting apolipoprotein A1 (apoA1) of HDL for oxidative modification and concurrent loss in cholesterol efflux and lecithin cholesterol acyl transferase activating activities, generating a "dysfunctional HDL" particle. We now show that (patho)physiologically relevant levels of MPO-catalyzed oxidation result in loss of noncholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve the loss of modified HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of saturable and specific binding to a novel unknown receptor independent of scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by NF-B activation and surface vascular cell adhesion molecule levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve methionine, tyrosine, or tryptophan, oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse cholesterol transport activities of the lipoprotein but also both the loss of non-cholesterol efflux related activities and the gain of pro-inflammatory functions. High density lipoprotein (HDL)3 is a complex mixture of cholesterol carrying lipoprotein particles built upon a predominantly apolipoprotein A1 (apoA1) backbone. HDL is currently thought to function primarily in mediating reverse cholesterol transport (RCT), the net transport of cholesterol from peripheral tissues to the liver for ultimate elimination into the intestinal lumen as biliary cholesterol for excretion in feces (1). RCT involves multiple biochemical processes, including both lipid poor apoA1 and HDL serving as acceptors of cholesterol efflux from peripheral cholesterol loaded cells, maturation of HDL from a nascent relatively cholesterol poor particle into a cholesterol-laden spherical form through interaction with lecithin cholesterol acyl transferase (LCAT), and delivery of cholesterol to liver and steroidogenic tissues through the HDL receptor, scavenger receptor B1 (SR-B1) (2).Although the RCT related functions of apoA1 and HDL are thought to primarily account for both the atheroprotective activity and the strong inverse association of HDL cholesterol and apoA1 levels and cardiovascular risks, other non-cholesterol efflux-related activities have a...

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Section: Discussionsupporting

confidence: 60%

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

Undurti

Huang

Lupica

et al. 2009

Journal of Biological Chemistry

Self Cite

238

178

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“…Last, MPO is secreted by activated leukocytes and is thought to mediate oxidative stress and atherogenesis 42. It has been associated with future coronary disease and HF in case‐control studies 43, 44. In our study, MPO predicted incident HF, in addition to all‐cause mortality.…”

Section: Discussionmentioning

confidence: 50%

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Lyass

Courchesne

et al. 2018

JAHA

221

228

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BackgroundThe discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk‐stratification methods and may be informative regarding biological pathways contributing to disease.Methods and ResultsWe used a discovery proteomic platform that targeted high‐value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable‐adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all‐cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P‐value ranges, 9.8×10−34 to 3.6×10−2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin‐like growth factor 1 (IGF1), insulin‐like growth factor binding protein 1 (IGFBP1), insulin‐like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N‐terminal pro‐b‐type natriuretic peptide, C‐reactive protein, and leptin were associated with incident heart failure, and C‐type lectin domain family 3 member B (CLEC3B; tetranectin), N‐terminal pro‐b‐type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin‐C were associated with all‐cause mortality in a multimarker model.ConclusionsWe identified numerous protein biomarkers that predicted cardiovascular outcomes and all‐cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

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“…Although there is a suggestion that MPO may be produced by atherosclerotic macrophages, there is also evidence that MPO may be derived from neutrophils in the vascular wall in atherosclerosis [72]. It has been demonstrated that the measurement of MPO levels may be useful in risk stratification of patients with atherosclerosis [78,79]. In addition, MPO polymorphism studies have demonstrated an increased risk for cardiovascular events in patients with chest pain [80].…”

Section: Pathophysiology Of Accelerated Atherosclerosis In Vasculitismentioning

confidence: 99%

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

Tervaert

2009

Clinical and Experimental Immunology

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SummaryPremature atherosclerosis has been observed during the course of different systemic inflammatory diseases such as rheumatoid arthritis and sytemic lupus erythematosus. Remarkably, relatively few studies have been published on the occurrence of accelerated atherosclerosis in patients with vasculitis. In giant cell arteritis (GCA), mortality because of ischaemic heart disease is not increased. In addition, intima media thickness (IMT) is lower in patients with GCA than in age-matched controls. In contrast, IMT is increased significantly in Takayasu arteritis, another form of large vessel vasculitis occurring in younger patients. In Takayasu arteritis and in Kawasaki disease, a form of medium-sized vessel vasculitis, accelerated atherosclerosis has been well documented. In small vessel vasculitis because of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis, cardiovascular diseases are a major cause of mortality. IMT measurements reveal conflicting results. During active disease these patients experience acceleration of the atherosclerotic process. However, when inflammation is controlled, these patients have atherosclerotic development as in healthy subjects. Several risk factors, such as diabetes and hypertension, are present more often in patients with vasculitis compared with healthy controls. In addition, steroids may be pro-atherogenic. Most importantly, many patients have impaired renal function, persistent proteinuria and increased levels of C-reactive protein, well-known risk factors for acceleration of atherosclerosis. Enhanced oxidation processes, persistently activated T cells and reduced numbers of regulatory T cells are among the many pathophysiological factors that play a role during acceleration of atherogenesis. Finally, autoantibodies that may be relevant for acceleration of atherosclerosis are found frequently in elevated titres in patients with vasculitis. Because patients have an increased risk for cardiovascular events, vasculitis should be treated with as much care as possible. In addition, treatment should be considered with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor-1 blockers, statins and acetylsalicyl acid. Finally, classical risk factors for cardiovascular disease should be monitored and treated as much as possible.

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Serum Myeloperoxidase Levels Are Associated With the Future Risk of Coronary Artery Disease in Apparently Healthy Individuals

Abstract: Elevated MPO levels predict future risk of CAD in apparently healthy individuals. This study suggests that inflammatory activation precedes the onset of overt CAD by many years.

Cited by 390 publications

References 29 publications

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

Modification of High Density Lipoprotein by Myeloperoxidase Generates a Pro-inflammatory Particle

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

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