Prognostic Value of Myeloperoxidase in Patients with Chest Pain

Brennan, Marie–Luise; Penn, Marc S.; Lente, Frederick Van; Nambi, Vijay; Shishehbor, Mehdi H.; Aviles, Ronnier J.; Goormastic, Marlene; Pepoy, Michael; McErlean, Ellen; Topol, Eric J.; Nissen, Steven E.; Hazen, Stanley L.

doi:10.1056/nejmoa035003

Cited by 937 publications

(506 citation statements)

References 27 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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234

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

234

178

View full text Add to dashboard Cite

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“…Interestingly, increased MPO levels are also observed in states of diseases believed to be unrelated to microbial infection, i.e., ischemia and reperfusion injury and acute coronary disease (29)(30)(31)(32)(33). In this regard, MPO has long been attributed to tissue injury, primarily through generation of oxidants.…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins

Lau

Mollnau

Eiserich

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

382

309

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Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with healthy individuals. Isolated PMNs bound free MPO by a CD11b͞CD18 integrin-dependent mechanism. PMNs exposed to MPO were characterized by increased tyrosine phosphorylation and p38 mitogen-activated protein kinase activation. Also, nuclear translocation of NF B in PMN was enhanced after incubation with MPO, as was surface expression of CD11b. Binding of PMN to MPO-coated fibronectin surfaces amplified PMN degranulation, as evidenced by increased release of MPO and elastase. MPO also augmented PMN-dependent superoxide (O 2 •؊ ) production, which was prevented by anti-CD11b antibodies, but not MPO inhibitors. Collectively, these results reveal that binding of MPO to CD11b͞CD18 integrins stimulates PMN signaling pathways to induce PMN activation in a mechanism independent of MPO catalytic activity. These cytokine-like properties of MPO thus represent an additional dimension of the proinflammatory actions of MPO in vascular disease.atherosclerosis ͉ cytokine ͉ endothelium ͉ leukocyte ͉ nitric oxide

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“…Circulating levels of protein 3-nitrotyrosine may serve as a biomarker to assess atherosclerosis risk as well as to monitor the vasculoprotective action of drugs. Interestingly, circulating MPO levels may also serve as predictor of cardiovascular risk (76). Thus, enhanced • NO consumption by either vascular wall͞inflammatory cell-derived O 2…”

Section: The Biological Significance Of Protein Tyrosine Nitrationmentioning

confidence: 99%

“…In this context, release and sequestration of neutrophil-derived MPO in specific tissue compartments during inflammation are important aspects of MPO distribution and nitration capacity in vivo (63). However, results involving MPO in mice should be cautiously extrapolated to human inflammatory disease; indeed, surprisingly, whereas MPO levels positively correlate with cardiovascular risk in humans (76), MPO knockout mice develop atherosclerosis more rapidly than WT (96). MPO or EPO overexpresses are not available yet, but in the future they may also provide clues to the role of MPO and EPO in pathology.…”

Section: Lessons From Geneticsmentioning

confidence: 99%