A key cardioprotective effect of high-density lipoprotein (HDL) involves the interaction of its major protein, apolipoprotein A-I (apoA-I), with ATP-binding cassette transporter A1 (ABCA1), a macrophage cholesterol exporter. ApoA I is thought to remove cholesterol from macrophages by a cascade of events. First it binds directly to ABCA1, activating signaling pathways, and then it binds to and solubilizes lipid domains generated by ABCA1.
HDL isolated from human atherosclerotic lesions and blood of subjects with established coronary artery disease contains elevated levels of 3-chlorotyrosine and 3-nitrotyrosine, two characteristic products of myeloperoxidase (MPO), a heme protein secreted by macrophages. Here we show that chlorination--but not nitration--of apoA-I by the MPO pathway impairs its ability to interact directly with ABCA1, to activate the Janus kinase 2 signaling pathway, and to promote efflux of cellular cholesterol. In contrast, oxidation of apoA-I has little effect on its ability to stabilize ABCA1 protein or to solubilize phospholipids.
Our results indicate that chlorination of apoA-I by the MPO pathway selectively inhibits two critical early events in cholesterol efflux: the binding of apoA-I to ABCA1 and activation of a key signaling pathway. Therefore, oxidation of apoA-I in the artery wall by MPO-generated chlorinating intermediates may contribute to atherogenesis by impairing cholesterol efflux from macrophages
Baohai Shao1, Chongren Tang1, Jay W. Heinecke1 and John F. Oram2,*
1 University of Washington, United States;
2 University of Washington Medical Center, United States
Vascular Endothelial Function Is Related to White Blood Cell Count and Myeloperoxidase Among Healthy Middle-Aged and Older Adults
Abstract—Endothelium-dependent dilation (EDD) is impaired with aging, but there is significant variability among healthy middle-aged and older adults. We tested the hypothesis that EDD is related to white blood cell (WBC) count in healthy men and women aged 55 to 75 years (n=48) who have a WBC count within the clinically normal range. The peak forearm blood flow response to intrabrachial artery infusion of acetylcholine was inversely related to WBC count (r=-0.38; P=0.004) and was 34% smaller in subjects with higher versus lower WBC count (more versus less than the median of 5.0x109 cells per liter; P=0.001).
Vascular smooth muscle responsiveness to NO (peak forearm blood flow response to sodium nitroprusside) was inversely related to WBC count (r=-0.30; P=0.02) but did not fully explain the associations with EDD. Inhibition of NO with NG-monomethyl-L-arginine reduced EDD in subjects with lower (-56%; P=0.01) but not higher WBC count. Tetrahydrobiopterin selectively improved EDD in subjects with higher WBC count (+35%; P=0.01) by increasing NO bioavailability. EDD was related (P<0.05) to neutrophil, eosinophil, and monocyte but not lymphocyte or basophil counts.
Myeloperoxidase, which is secreted by neutrophils and monocytes, consumes NO and produces molecules that oxidize tetrahydrobiopterin, was inversely related to EDD (r=-0.35; P=0.02), and was 42% higher in subjects with a higher WBC count (P=0.02). No other factors contributed to the relation between EDD and WBC count. Among healthy middle-aged and older adults, impaired EDD is related to higher neutrophil, eosinophil, and monocyte-based WBC count mediated by reduced responsiveness to NO and increased myeloperoxidase-associated reductions in tetrahydrobiopterin and NO bioavailability.
Ashley E. Walker; Sara Marian Seibert; Anthony J. Donato; Gary L. Pierce; and Douglas R. Seals*
From the Department of Integrative Physiology, University of Colorado, Boulder, Colo
Vascular smooth muscle responsiveness to NO (peak forearm blood flow response to sodium nitroprusside) was inversely related to WBC count (r=-0.30; P=0.02) but did not fully explain the associations with EDD. Inhibition of NO with NG-monomethyl-L-arginine reduced EDD in subjects with lower (-56%; P=0.01) but not higher WBC count. Tetrahydrobiopterin selectively improved EDD in subjects with higher WBC count (+35%; P=0.01) by increasing NO bioavailability. EDD was related (P<0.05) to neutrophil, eosinophil, and monocyte but not lymphocyte or basophil counts.
Myeloperoxidase, which is secreted by neutrophils and monocytes, consumes NO and produces molecules that oxidize tetrahydrobiopterin, was inversely related to EDD (r=-0.35; P=0.02), and was 42% higher in subjects with a higher WBC count (P=0.02). No other factors contributed to the relation between EDD and WBC count. Among healthy middle-aged and older adults, impaired EDD is related to higher neutrophil, eosinophil, and monocyte-based WBC count mediated by reduced responsiveness to NO and increased myeloperoxidase-associated reductions in tetrahydrobiopterin and NO bioavailability.
Ashley E. Walker; Sara Marian Seibert; Anthony J. Donato; Gary L. Pierce; and Douglas R. Seals*
From the Department of Integrative Physiology, University of Colorado, Boulder, Colo
Usefulness of Myeloperoxidase Levels in Healthy Elderly Subjects to Predict Risk of Developing Heart Failure
Increased systemic myeloperoxidase (MPO) has been associated with both the presence and severity of heart failure (HF). This study tested the hypothesis that increased systemic MPO in apparently healthy elderly subjects may predict increased risk of developing HF. Systemic MPO was measured in all available samples from the 1992 to 1993 visit of the Cardiovascular Health Study (CHS). After excluding subjects without available blood samples or with a history of prevalent HF, myocardial infarction (MI), or stroke, 3,733 subjects were included. A total of 569 subjects developed incident HF during 7.2 ± 2.3 years of follow-up. Patients in the highest MPO quartile (>432 pmol/L) showed higher risk of developing incident HF after adjusting for MI, age, gender, systolic blood pressure, smoking, low-density lipoprotein cholesterol, diabetes mellitus, and any subclinical cardiovascular disease (hazard ratio 1.34, 95% confidence interval 1.06 to 1.72, p = 0.013). However, the relation was more apparent after censoring subjects with incident MI before incident HF, even when adjusted for C-reactive protein and cystatin C (hazard ratio 1.46, 95% confidence interval 1.08 to 1.97, p = 0.02). Interestingly, stratified analyses showed that the relation between increased MPO and HF risk was stronger in subjects without traditional cardiovascular risk factors (≤75 years old, systolic blood pressure ≤136 mm Hg, no subclinical cardiovascular disease, and no diabetes mellitus). In conclusion, an independent association between increased MPO and the development of HF in apparently healthy elderly subjects was observed, particularly beyond MI and traditional cardiac risk factors.
Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of a number of reactive oxidant species and impacts on nitric oxide through complex mechanisms, including direct catalytic consumption resulting in endothelial dysfunction.1,2 Myeloperoxidase has been shown to provide prognostic value in the setting of chest pain and acute coronary syndromes.3–5 Recent studies of the community-based European Prospective Investigation of Cancer (EPIC)/Nolfork population also reported that systemic MPO independently predicted risk of the development of incident cardiovascular disease and death in apparently healthy middle-aged subjects.6 A potential pathogenic role of MPO in the development of left ventricular dysfunction and heart failure (HF) was also emerging.7–9 In animal models, MPO knockout mice showed an important role of MPO in facilitating HF disease progression.10 In humans, systemic MPO was increased in patients with established chronic systolic HF and correlated with diastolic dysfunction independent of age and plasma B-type natriuretic peptide.8 Recent studies also showed that systemic MPO in subjects with myocardial infarction (MI)7 or chronic systolic HF9 may predict long-term adverse clinical events. Here, we hypothesized that MPO may be associated with the long-term risk of developing HF in apparently healthy elderly subjects.
Am J Cardiol. 2009 May 1; 103(9): 1269–1274.
Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of a number of reactive oxidant species and impacts on nitric oxide through complex mechanisms, including direct catalytic consumption resulting in endothelial dysfunction.1,2 Myeloperoxidase has been shown to provide prognostic value in the setting of chest pain and acute coronary syndromes.3–5 Recent studies of the community-based European Prospective Investigation of Cancer (EPIC)/Nolfork population also reported that systemic MPO independently predicted risk of the development of incident cardiovascular disease and death in apparently healthy middle-aged subjects.6 A potential pathogenic role of MPO in the development of left ventricular dysfunction and heart failure (HF) was also emerging.7–9 In animal models, MPO knockout mice showed an important role of MPO in facilitating HF disease progression.10 In humans, systemic MPO was increased in patients with established chronic systolic HF and correlated with diastolic dysfunction independent of age and plasma B-type natriuretic peptide.8 Recent studies also showed that systemic MPO in subjects with myocardial infarction (MI)7 or chronic systolic HF9 may predict long-term adverse clinical events. Here, we hypothesized that MPO may be associated with the long-term risk of developing HF in apparently healthy elderly subjects.
Am J Cardiol. 2009 May 1; 103(9): 1269–1274.
C-Reactive Protein Stimulates Myeloperoxidase Release from Polymorphonuclear Cells and Monocytes: Implications for Acute Coronary Syndromes
Abstract
Background: C-reactive protein (CRP), the prototypic marker of inflammation, is present in atherosclerotic plaques and appears to promote atherogenesis. Also, CRP has been localized to monocytes and tissue macrophages, which are present in the necrotic core of lesions prone to plaque rupture. Leukocyte-derived myeloperoxidase (MPO), primarily hosted in human polymorphonuclear cells (PMNs), has also been shown to be present in human atherosclerotic lesions. Because MPO and CRP concentrations are increased in acute coronary syndrome (ACS) patients and predict poor outcomes, we tested the effect of CRP on MPO release from PMNs and monocytes.
Methods: We treated human PMNs and monocytes with CRP (25 and 50 mg/L for 6 h) and measured MPO release as total mass and activity in culture supernatants. We also measured nitro-tyrosinylation (NO2-Tyr) of LDL as an indicator of biological activity of CRP-mediated MPO release. Furthermore, we explored the effect of human CRP on MPO release in the rat sterile pouch model.
Results: CRP treatment significantly increased release of MPO (both mass and activity) from human PMNs as well as monocytes (P < 0.05) and caused NO2-Tyr of LDL. Human CRP injection in rats resulted in increased concentrations of MPO in pouch exudates (P < 0.05), thus confirming our in vitro data.
Conclusions: CRP stimulates MPO release both in vitro and in vivo, providing further cogent data for the proinflammatory effect of CRP. These results might further support the role of CRP in ACS.
Uma Singha, Sridevi Devaraj and Ishwarlal Jialal
Department of Medical Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA
Background: C-reactive protein (CRP), the prototypic marker of inflammation, is present in atherosclerotic plaques and appears to promote atherogenesis. Also, CRP has been localized to monocytes and tissue macrophages, which are present in the necrotic core of lesions prone to plaque rupture. Leukocyte-derived myeloperoxidase (MPO), primarily hosted in human polymorphonuclear cells (PMNs), has also been shown to be present in human atherosclerotic lesions. Because MPO and CRP concentrations are increased in acute coronary syndrome (ACS) patients and predict poor outcomes, we tested the effect of CRP on MPO release from PMNs and monocytes.
Methods: We treated human PMNs and monocytes with CRP (25 and 50 mg/L for 6 h) and measured MPO release as total mass and activity in culture supernatants. We also measured nitro-tyrosinylation (NO2-Tyr) of LDL as an indicator of biological activity of CRP-mediated MPO release. Furthermore, we explored the effect of human CRP on MPO release in the rat sterile pouch model.
Results: CRP treatment significantly increased release of MPO (both mass and activity) from human PMNs as well as monocytes (P < 0.05) and caused NO2-Tyr of LDL. Human CRP injection in rats resulted in increased concentrations of MPO in pouch exudates (P < 0.05), thus confirming our in vitro data.
Conclusions: CRP stimulates MPO release both in vitro and in vivo, providing further cogent data for the proinflammatory effect of CRP. These results might further support the role of CRP in ACS.
Uma Singha, Sridevi Devaraj and Ishwarlal Jialal
Department of Medical Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA
Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events.
We investigated the association of serum MPO with the ankle-brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African-Americans and non-Hispanic white individuals. Participants included 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic white individuals (mean age 59 years, 57% women) belonging to hypertensive sibships.
Serum levels of Myeloperoxidase MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD was defined as an ABI < 0.90. Multivariable regression analysis using generalized estimating equations were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and the presence of PAD in African-Americans (p = 0.004 and p = 0.005, respectively) and in non-Hispanic white individuals (p = 0.001 and p = 0.016, respectively).
After additional adjustment for conventional risk factors (diabetes, smoking status, total and high-density lipoprotein cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher Myeloperoxidase levels remained significantly associated with lower ABI and the presence of PAD in both African-Americans (p = 0.008 and p = 0.010, respectively) and non-Hispanic white individuals (p = 0.001 and p = 0.018, respectively).
We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic white individuals
Ali Z, Sarcia P, Mosley TH, Kondragunta V, Kullo IJ.
Division of Cardiovascular Diseases, Mayo Clinic
We investigated the association of serum MPO with the ankle-brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African-Americans and non-Hispanic white individuals. Participants included 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic white individuals (mean age 59 years, 57% women) belonging to hypertensive sibships.
Serum levels of Myeloperoxidase MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD was defined as an ABI < 0.90. Multivariable regression analysis using generalized estimating equations were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and the presence of PAD in African-Americans (p = 0.004 and p = 0.005, respectively) and in non-Hispanic white individuals (p = 0.001 and p = 0.016, respectively).
After additional adjustment for conventional risk factors (diabetes, smoking status, total and high-density lipoprotein cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher Myeloperoxidase levels remained significantly associated with lower ABI and the presence of PAD in both African-Americans (p = 0.008 and p = 0.010, respectively) and non-Hispanic white individuals (p = 0.001 and p = 0.018, respectively).
We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic white individuals
Ali Z, Sarcia P, Mosley TH, Kondragunta V, Kullo IJ.
Division of Cardiovascular Diseases, Mayo Clinic
Neutrophil activation precedes myocardial injury in patients with acute myocardial infarction
Department of Cardiology and Cardiovascular Research Center, University Heart Center, D-20246 Hamburg, Germany.
Myeloperoxidase (MPO), a heme protein abundantly expressed and secreted by polymorphonuclear neutrophils (PMN), has emerged as a critical mediator in coronary atherosclerosis. Retrospective analyses have suggested that free plasma levels of Myeloperoxidase predict adverse outcome in patients with low troponin T (TnT) levels who subsequently experience myocardial injury.
The aim of this study was to evaluate the time course of Myeloperoxidase plasma levels in the early stages of acute myocardial infarction (AMI). Of 155 consecutive patients hospitalized for acute coronary syndromes, 38 presenting within 2 h of the onset of symptoms and subsequently diagnosed for AMI were included in the study. Serial blood samples taken between 1 and 24 h after the onset of chest pain were analyzed for Myeloperoxidase, TnT, creatine kinase MB, myoglobin, and high sensitive C-reactive protein. Fifty patients with angiographically proven but stable coronary artery disease (CAD) served as controls.
In contrast to all other investigated markers, Myeloperoxidase was markedly elevated within 2 h of symptom onset in patients with AMI. Heparin, which is known to increase MPO plasma levels in patients with stable CAD, had no effect on MPO plasma levels in AMI patients. High levels of Myeloperoxidase MPO plasma levels at the time of admission and the rapid peak of free plasma Myeloperoxidase levels after the onset of symptoms suggests that PMN activation is an early event in AMI and potentially precedes myocardial injury.
Myeloperoxidase (MPO), a heme protein abundantly expressed and secreted by polymorphonuclear neutrophils (PMN), has emerged as a critical mediator in coronary atherosclerosis. Retrospective analyses have suggested that free plasma levels of Myeloperoxidase predict adverse outcome in patients with low troponin T (TnT) levels who subsequently experience myocardial injury.
The aim of this study was to evaluate the time course of Myeloperoxidase plasma levels in the early stages of acute myocardial infarction (AMI). Of 155 consecutive patients hospitalized for acute coronary syndromes, 38 presenting within 2 h of the onset of symptoms and subsequently diagnosed for AMI were included in the study. Serial blood samples taken between 1 and 24 h after the onset of chest pain were analyzed for Myeloperoxidase, TnT, creatine kinase MB, myoglobin, and high sensitive C-reactive protein. Fifty patients with angiographically proven but stable coronary artery disease (CAD) served as controls.
In contrast to all other investigated markers, Myeloperoxidase was markedly elevated within 2 h of symptom onset in patients with AMI. Heparin, which is known to increase MPO plasma levels in patients with stable CAD, had no effect on MPO plasma levels in AMI patients. High levels of Myeloperoxidase MPO plasma levels at the time of admission and the rapid peak of free plasma Myeloperoxidase levels after the onset of symptoms suggests that PMN activation is an early event in AMI and potentially precedes myocardial injury.
Myeloperoxidase, modified lipoproteins, and atherogenesis.
Departments of Cell Biology and Cardiovascular Medicine, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH.
Numerous lines of evidence implicate a role for Myeloperoxidase (MPO) in the pathogenesis of atherosclerosis. Enriched within vulnerable plaque, Myeloperoxidase MPO serves as an enzymatic source of eicosanoids and bioactive lipids and generates atherogenic forms of both low- and high-density lipoproteins. These factors likely contribute to clinical studies demonstrating that increased systemic levels of Myeloperoxidase MPO and its oxidation products predict increased cardiovascular risk. As a result, interest has focused on the potential to target MPO for the development of new risk markers, imaging, and therapies to prevent cardiovascular events.
Numerous lines of evidence implicate a role for Myeloperoxidase (MPO) in the pathogenesis of atherosclerosis. Enriched within vulnerable plaque, Myeloperoxidase MPO serves as an enzymatic source of eicosanoids and bioactive lipids and generates atherogenic forms of both low- and high-density lipoproteins. These factors likely contribute to clinical studies demonstrating that increased systemic levels of Myeloperoxidase MPO and its oxidation products predict increased cardiovascular risk. As a result, interest has focused on the potential to target MPO for the development of new risk markers, imaging, and therapies to prevent cardiovascular events.
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