Formation of Dysfunctional High-Density Lipoprotein by Myeloperoxidase

doi:10.1016/j.tcm.2005.06.004

Trends in Cardiovascular Medicine

Volume 15, Issue 6, August 2005, Pages 212-219

https://doi.org/10.1016/j.tcm.2005.06.004 Get rights and content

Recent studies identify the presence of high-density lipoprotein (HDL) particles in patients with cardiovascular disease, which are “dysfunctional,” lacking in typical atheroprotective properties, and promoting proinflammatory effects. The mechanisms for generating dysfunctional HDL have been unclear. New evidence points to a role for myeloperoxidase (MPO)-generated oxidants as participants in rendering HDL dysfunctional within human atherosclerotic plaque. Myeloperoxidase was recently shown to bind to HDL within human atherosclerotic lesions, and biophysical studies reveal MPO binding occurs via specific interactions with apolipoprotein (apo) A-I, the predominant protein of HDL. This likely facilitates the observed selective targeting of apoA-I for site-specific chlorination and nitration by MPO-generated reactive oxidants in vivo. One apparent consequence of MPO-catalyzed apoA-I oxidation includes the functional impairment of the ability of HDL to promote cellular cholesterol efflux via the adenosine triphosphate binding cassette-1 transport system. Myeloperoxidase-mediated loss of the atheroprotective functional properties of HDL may thus provide a novel mechanism linking inflammation and oxidative stress to the pathogenesis of atherosclerosis.

Section snippets

Dysfunctional Forms of High-Density Lipoprotein

Despite the consistent demonstration that a low plasma HDL is a strong predictor of clinical risk, it is apparent that many patients with “normal” or even “elevated” plasma HDL experience clinical events. In fact, nearly half of the clinical events in the Framingham cohort occurred in subjects with plasma HDL concentrations ≥40 mg/dL (Kwiterovich 1998). It has been proposed that HDL with impaired functional properties within subjects of this cohort may lead to either a loss of protective

High-Density Lipoprotein as a Selective Target of Oxidation in the Artery Wall

Low-density lipoprotein oxidation is widely believed to play an important role in the development of atherosclerotic plaque. Native LDL has little effect on cells of the arterial wall, whereas oxidatively modified forms of LDL induce numerous proatherosclerotic effects, including promotion of cholesterol deposition and foam cell formation (Parthasarathy et al. 1989, Podrez et al. 1999, Podrez et al. 2000, Glass and Witztum, 2001, Chisholm and Steinberg, 2000). Whereas considerable interest has

Myeloperoxidase Binding to High-Density Lipoprotein in Vivo Facilitates Oxidative Modification and Functional Inactivation of the Lipoprotein

Multiple lines of evidence support a role for MPO as a major enzymatic catalyst for apoA-I oxidation in vivo. Foremost, MPO is the only known enzyme in mammals capable of generating chlorinating oxidants (Hazen and Heinecke 1997), and multiple studies with the use of MPO knockout mice in various inflammatory models confirm the essential role of MPO in generation of ClTyr in vivo (Brennan et al. 2001, Brennan et al. 2003, Askari et al. 2003, Zhang et al. 2002). The selective enrichment of ClTyr

Identification of Sites of Nitration and Chlorination on Apolipoprotein A-I Recovered from Human Atherosclerotic Plaque

Specific sites on apoA-I that serve as both targets for modification within atheroma, as well as preferred sites for MPO catalyzed modifications, have now been reported (Zheng et al. 2005) (Figure 3). Tandem mass spectrometry analyses of MPO reaction mixtures with intact HDL identify two tyrosine residues within helix 8 and 7, respectively, of apoA-I that serve as preferred targets for both nitration and chlorination, Y192 and Y166. Dose response studies with HDL as a target demonstrates a

Oxidized Cross-Linking of High-Density Lipoprotein

Not all oxidant modifications of HDL may result in detrimental functional consequences. Wang et al. (1998) reported that HDL exposed to a tyrosyl radical generating system in vitro produces a lipoprotein that is more effective than native HDL in promoting ABCA-1-dependent cholesterol efflux from lipid-laden fibroblasts and macrophages. Formation of cross-linked heterodimers composed of apoA-I and apoA-II reportedly account for the facilitated efflux activity in the oxidized HDL preparation.

Implications and Future Directions

Substantial evidence exists supporting a role for both MPO- and NO-derived oxidant pathways as contributors to cardiovascular disease in humans (Shishehbor et al. 2003a, Shishehbor et al. 2003b, Zhang et al. 2001, Brennan et al. 2003, Baldus et al. 2003, Vita et al. 2004, Eiserich et al. 2002, Baldus et al. 2004, Asselbergs et al. 2004, Loscalzo, 2001, Harrison et al. 2003). It is thus remarkable that within the past year, a constellation of studies collectively provided compelling evidence for

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As a new marker of inflammation and lipid metabolism, the ratio of myeloperoxidase to high density lipoprotein (MPO/HDL) has been reported in the field of cardiovascular disease. However, the effect of MPO/HDL on acute ischemic stroke (AIS) is not clear. The purpose of this study was to explore the prognostic value of MPO/HDL level in patients with AIS.
This study conducted a retrospective analysis of 363 patients diagnosed with AIS. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS). The short-term functional outcome was evaluated with modified Rankin Scale (mRS) 90 days after admission. Spearman correlation analysis was used to evaluate the correlation between MPO/HDL and NIHSS scores. The predictive value of MPO, HDL and MPO/HDL to AIS was evaluated by receiver operating characteristic curve (ROC).
The level of MPO/HDL in patients with NIHSS score ≥ 4 was significantly higher than that in patients with NIHSS score < 4 (P < 0.001). MPO and MPO/HDL were positively correlated with NIHSS score (P < 0.001), while HDL was negatively correlated with NIHSS score (P < 0.001). During 90-day follow-up, multivariate Logistic regression analysis showed that increased MPO/HDL levels were associated with 90-day functional outcomes. ROC showed that compared with MPO and HDL, MPO/HDL had the highest predictive value for 90-day functional prognosis in patients with AIS (AUC = 0.9825).
The level of serum MPO/HDL may be potential prognostic biomarker in AIS 90 days.
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Low HDL-cholesterol (HDL-C) concentrations are a typical trait of the dyslipidemia associated with chronic kidney disease (CKD). In this condition, plasma HDLs are characterized by alterations in structure and function, and these particles can lose their atheroprotective functions, e.g., the ability to promote cholesterol efflux from peripheral cells, anti-oxidant and anti-inflammatory proprieties and they can even become dysfunctional, i.e., exactly damaging. The reduction in plasma HDL-C levels appears to be the only lipid alteration clearly linked to the progression of renal disease in CKD patients. The association between the HDL system and CKD development and progression is also supported by the presence of genetic kidney alterations linked to HDL metabolism, including mutations in the APOA1, APOE, APOL and LCAT genes. Among these, renal disease associated with LCAT deficiency is well characterized and lipid abnormalities detected in LCAT deficiency carriers mirror the ones observed in CKD patients, being present also in acquired LCAT deficiency. This review summarizes the major alterations in HDL structure and function in CKD and how genetic alterations in HDL metabolism can be linked to kidney dysfunction. Finally, the possibility of targeting the HDL system as possible strategy to slow CKD progression is reviewed.
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The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown.
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This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH.
Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P < 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P < 0.001), PCSK9 inhibitor (P < 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P < 0.001), cardiac (P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P < 0.001) and of subsequent (P < 0.001) composite outcomes in subjects with severe FH.
Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.
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Review articleFormation of Dysfunctional High-Density Lipoprotein by Myeloperoxidase

Section snippets

Dysfunctional Forms of High-Density Lipoprotein

High-Density Lipoprotein as a Selective Target of Oxidation in the Artery Wall

Myeloperoxidase Binding to High-Density Lipoprotein in Vivo Facilitates Oxidative Modification and Functional Inactivation of the Lipoprotein

Identification of Sites of Nitration and Chlorination on Apolipoprotein A-I Recovered from Human Atherosclerotic Plaque

Oxidized Cross-Linking of High-Density Lipoprotein

Implications and Future Directions

J Biol Chem

Atherosclerosis

Free Radic Biol Med

J Biol Chem

J Lipid Res

Cell

Am J Med

J Biol Chem

J Lipid Res

J Lipid Res

J Biol Chem

J Biol Chem

Atherosclerosis

J Biol Chem

J Biol Chem

J Biol Chem

Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment

Circulation

Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction

J Exp Med

Prognostic value of myeloperoxidase in patients with chest pain

N Engl J Med

High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits

Lab Invest

Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes

Circulation

Antiinflammatory properties of HDL

Circ Res

The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport

Proc Natl Acad Sci USA

Apolipoprotein A-I(Milano) and apolipoprotein A-I(Paris) exhibit an antioxidant activity distinct from that of wild-type apolipoprotein A-I

Biochemistry

Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein

Circulation

High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors

Proc Natl Acad Sci USA

Increased atherosclerosis in myeloperoxidase-deficient mice

J Clin Invest

Prognostic value of myeloperoxidase in patients with chest pain

N Engl J Med

The oxidative modification hypothesis of atherogenesis: an overview

Free Radic Biol Med

Review article
Formation of Dysfunctional High-Density Lipoprotein by Myeloperoxidase