Hypochlorite oxidation causes cross-lingking of Lp(a)

O'Connell, Anita; Gieseg, Steven P.; Stanley, Keith K.

doi:10.1016/0925-4439(94)90076-0

Cited by 28 publications

(14 citation statements)

References 33 publications

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“…Consistent with previous reports (13,14), in vitro treatment of LDL with HOCl (400 molecules of oxidant per particle) resulted in non-disulfide cross-linked apo B with little if any apo B monomer remaining (Fig. 6 a , lanes 1 and 2 ).…”

Section: Resultssupporting

confidence: 92%

“…6) indicate that lipoproteins are among these proteins, as indicated by the presence of HOP-1-recognized material in the apo B-containing lipoprotein fraction prepared from plaque homogenate. The material recognized was poorly mobile during PAGE, fully consistent with HOCl modification of apo B in human lesions, which results in increased crosslinking of LDL's apo B with increasing oxidant-to-lipoprotein ratios (13,14). However, further experiments are required to demonstrate unambiguously such modification of LDL's apo B in atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 87%

“…Although it is commonly assumed that lipid peroxidation precedes, and to some extent causes, oxidative modification of apolipoprotein B-100, hypochlorite (HOCl) can transform the lipoprotein into a high uptake form without significant lipid (per)oxidation. Apo B-100, the single major protein associated with LDL, is the main target for this oxidant (12,13) and becomes aggregated and crosslinked (13,14). HOCl is an oxidant produced from H 2 O 2 and chloride by myeloperoxidase (MPO, E.C.…”

Section: Introductionmentioning

confidence: 99%

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Presence of hypochlorite-modified proteins in human atherosclerotic lesions.

Hazell¹,

Arnold²,

Flowers³

et al. 1996

J. Clin. Invest.

572

363

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Oxidation of LDL may contribute to atherogenesis, though the nature of the in vivo oxidant(s) remains obscure. Myeloperoxidase, the enzyme responsible for hypochlorous acid/hypochlorite (HOCl) production in vivo, is present in active form in human atherosclerotic lesions, and HOCl aggregates and transforms LDL into a high-uptake form for macrophages in vitro. Here we demonstrate HOCl-modified proteins in human lesions using an mAb raised against HOCl-modified LDL that recognizes HOCl-oxidized proteins but does not cross-react with Cu

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Presence of hypochlorite-modified proteins in human atherosclerotic lesions.

Hazell¹,

Arnold²,

Flowers³

et al. 1996

J. Clin. Invest.

572

363

View full text Add to dashboard Cite

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“…Reportedly, hypoxLDLs show an increased tendency of self-aggregation, which can be prevented by reductive methylation before treatment with hypochlorite (hypmetLDLs). 25 In our hands, SDS-PAGE never revealed the formation of the covalently cross-linked high molecular weight species reported by others, 26 and the gel filtration profiles were virtually identical to unmodified controls. Tracings a to d in Figure 1 show the effect of hypoxLDL (REM 1.79) on washed human platelets in suspension, including a control aggregation obtained with ADP.…”

Section: Resultsmentioning

confidence: 71%

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Volf

Bielek

Moeslinger

et al. 2000

ATVB

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Abstract-Conflicting reports exist about the effects of mildly or extensively oxidized low density lipoproteins (LDLs) on the reactivity of human platelets. This platelet response is mainly caused by modification of the protein and lipid moiety, giving rise to very differently modified species with hardly predictable properties. The aim of this study was to prepare oxidized LDL with modifications essentially restricted to the protein moiety and to determine the eventual platelet responses. We treated LDL at 0°C for 10 minutes with a 60-to 1000-fold molar excess of sodium hypochlorite in borate buffer in the presence of the radical scavenger butylated hydroxytoluene. Under these conditions, neither fragmentation of apolipoprotein B-100 nor formation of LDL aggregates was observed, and lipid oxidation products did not exceed the amount present in untreated LDLs. The degree of modification and the respective effects on platelet function were highly reproducible. Hypochlorite-modified LDLs act as strong platelet agonists, inducing morphological changes, dense granule release, and irreversible platelet aggregation. The evoked platelet effects are completely suppressed by inhibitors of the phosphoinositide cycle but not by EDTA or acetylsalicylic acid. Most likely, these effects are transmitted via high-affinity binding to a single class of sites, which does not recognize native or acetylated LDL. Obviously, modified lysines, and the secondary lipid modifications derived from them, are not essential for this interaction. We conclude that bioactive oxidized lipids are not directly involved in the stimulation of platelets by hypochlorite-modified LDLs. Key Words: atherosclerosis Ⅲ oxidized LDL Ⅲ apoB-100 Ⅲ human platelets Ⅲ platelet aggregation P latelet-vessel wall interaction (adhesion) and plateletplatelet interaction (aggregation) play a central role in vascular occlusion but are also involved in the earlier stages of development of atherosclerotic plaques. 1 Therefore, conditions leading to altered platelet function are accompanied with an enhanced risk of atherosclerosis and thrombosis. 2 Among others, severe disorders of plasma lipids lead to enhanced platelet reactivity. In particular, it has been known for Ͼ25 years that platelets from hyperlipidemic patients are hyperreactive. 3 Furthermore, LDLs from patients with homozygous familial hypercholesterolemia show enhanced susceptibility to oxidative modification, 4 thus generating a form that is substantially more atherogenic than unmodified LDLs. 5 Native LDLs (nLDLs) reportedly stimulate human platelets, 6,7 but minimally modified LDLs rather than nLDLs may be responsible for these effects. 8,9 LDLs oxidized in vitro by various agents (oxLDLs) showed even more pronounced platelet activation. 10 Because activated platelets may themselves contribute to oxidative modification of LDLs, 11 the platelet-stimulatory effect of plasma lipoproteins is potentially a key event in atherogenesis.Free radicals as well as nonradical oxidants are involved in the oxidative modif...

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“…Using interferon γ (IFN‐γ)/lipopolysaccharide (LPS) stimulated macrophages we examined the effects of native Lp(a) and hypochlorite (HOCl) oxidized Lp(a) on inducible NO synthesis. During our experiments HOCl oxidized Lp(a) was used because HOCl might be released from activated neutrophils in vivo [36], and the occurrence of HOCl oxidized lipoprotein within atherosclerotic lesion has been demonstrated [37]. The inhibition of inducible NO synthesis by ox‐Lp(a) might initiate macrophage proliferation since NO decreases cell proliferation by increasing the rate of apoptosis [38].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of inducible nitric oxide synthesis by oxidized lipoprotein(a) in a murine macrophage cell line

Moeslinger¹,

Friedl²,

Volf³

et al. 2000

FEBS Letters

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Increased plasma levels of human lipoprotein(a) (Lp(a)) are highly correlated with the development of atherosclerotic lesions. During our study, we investigated the effects of native and hypochlorite oxidized lipoprotein(a) (ox-Lp(a)) on nitric oxide production by the inducible nitric oxide synthase (iNOS) in lipopolysaccharide/interferon stimulated mouse macrophages (J774A.1). Ox-Lp(a) (0^2 W Wg/ml) induces a dose dependent inhibition of inducible nitric oxide synthesis. iNOS protein expression showed a dose dependent reduction as revealed by immunoblotting when cells were incubated with increasing amounts of ox-Lp(a). Ox-Lp(a) decreases iNOS mRNA synthesis as shown by reverse transcription-polymerase chain reaction. Ox-Lp(a) induced iNOS inhibition might contribute to the development of atherosclerotic lesions by reducing the antiatherogenic effects of nitric oxide. ß

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Hypochlorite oxidation causes cross-lingking of Lp(a)

Cited by 28 publications

References 33 publications

Presence of hypochlorite-modified proteins in human atherosclerotic lesions.

Presence of hypochlorite-modified proteins in human atherosclerotic lesions.

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Inhibition of inducible nitric oxide synthesis by oxidized lipoprotein(a) in a murine macrophage cell line

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