Human Low Density Lipoprotein as a Target of Hypochlorite Generated by Myeloperoxidase

Jerlich, A.; Fabjan, Judith S.; Tschabuschnig, S.; Smirnova, Angela V.; Horáková, Ľubica; Hayn, Marianne; Auer, H.; Guttenberger, Helmut; Leis, Hans Jörg; Tatzber, Franz; Waeg, Georg; Schaur, R. J.

doi:10.1016/s0891-5849(97)00439-5

Cited by 52 publications

(33 citation statements)

References 27 publications

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“…32 This possibility is strengthened by the observation that some monoclonal antibodies, which do not cross-react with other types of modified LDLs, also recognize epitopes on other hypochloritemodified proteins. 14,33,34 Furthermore, treatment with hypochlorite can also transform other proteins into plateletaggregating agents. This includes delipidated HSA and fibrinogen, oxidized with NaOCl/protein ratios between 500 and 1000, whereas several other proteins are ineffective (authors' unpublished data, 2000).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…It is generally accepted that hypochlorite preferentially oxidizes apoB 15,36 with little or no lipid peroxidation, 15,34,37 that ␣-tocopherol is not depleted, 15,36 and that LDL cholesterol is not oxidized. 15,38 Extensive lipid peroxidation requires prolonged treatment of LDLs or liposomes with NaOCl at 37°C.…”

Section: Discussionmentioning

confidence: 99%

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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“…41,44,45 One mechanism proposed by Panasenko 46 involves homolytic cleavage of preformed lipid hydroperoxides by HOCl to generate alkoxyl radicals. More recently, it has been reported that LDL-associated chloramines break down to produce radicals that can initiate lipid peroxidation.…”

Section: Mpo-dependent Oxidation Of Ldlmentioning

confidence: 99%

Oxidation of LDL by Myeloperoxidase and Reactive Nitrogen Species

Carr

McCall

Frei

2000

ATVB

364

205

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Abstract-Oxidative modification of low density lipoprotein (LDL) appears to play an important role in atherogenesis.Although the precise mechanisms of LDL oxidation in vivo are unknown, several lines of evidence implicate myeloperoxidase and reactive nitrogen species, in addition to ceruloplasmin and 15-lipoxygenase. Myeloperoxidase generates a number of reactive species, including hypochlorous acid, chloramines, tyrosyl radicals, and nitrogen dioxide. Key Words: low density lipoproteins Ⅲ myeloperoxidase Ⅲ reactive nitrogen species Ⅲ vitamin C Ⅲ vitamin E T he hypothesis that oxidative stress plays an important role in the pathogenesis of atherosclerosis has gained considerable support. Although there are many determinants in the development of an atherosclerotic lesion, substantial in vitro evidence links LDL oxidation to potentially atherogenic processes at the molecular and cellular level. 1-3 However, the in vivo mechanism(s) of the initiation and progression of LDL oxidation is presently unclear and is a topic of much research. The most relevant information concerning this mechanism has come from immunohistochemical and biochemical analyses of animal and human atherosclerotic lesions and lipoproteins extracted from these lesions. Ceruloplasmin, 15-lipoxygenase, myeloperoxidase (MPO), and inducible (in addition to endothelial) nitric oxide synthase (NOS) have been found in animal and human lesions and can cause or contribute to LDL oxidation in vitro. 2,4 -10 With respect to a role for ceruloplasmin in in vivo LDL oxidation, specific markers of metal ion-catalyzed protein damage are not elevated in early or intermediate lesions, in contrast to advanced lesions. 9,11 Immunohistochemical detection of aldehyde-modified LDL in human and animal lesions 12,13 also has been used as evidence for metal ionmediated oxidation; however, the specificity of antibodies raised against aldehyde-modified or copper-oxidized LDL has been questioned, because these can cross-react with LDL modified by hypochlorous acid (HOCl). 14 Therefore, it appears unlikely that ceruloplasmin and other sources of redoxactive metal ions contribute significantly to LDL oxidation in vivo during the early stages of atherosclerotic lesion development.The role of 15-lipoxygenase in LDL oxidation and atherogenesis is controversial, because the mechanism by which the intracellular enzyme "seeds" extracellular LDL with hydroperoxides is unclear. 15,16 Furthermore, there is limited evidence for the presence of 15-lipoxygenase-modified lipids in lesions, because only small increases in the S/R enantiomeric ratio of lipid hydro(pero)xides were detected. 17,18 Nevertheless, immunohistochemical studies have demonstrated the presence of 15-lipoxygenase in macrophage-rich regions of human and rabbit atherosclerotic lesions, 19,20 and epitopes of oxidized LDL colocalize with 15-lipoxygenase. 20 Interestingly, cholesterol-fed transgenic rabbits overexpressing the human 15-lipoxygenase gene in macrophages develop significantly less atherosclerosis than do the...

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“…In this case, the oxidation reaction can be followed by observing changes in the physicochemical and biological properties of the LDL (Jerlich et al 1998(Jerlich et al , 2000a.…”

Section: Discussionmentioning

confidence: 99%

Nicotine-enhanced oxidation of low-density lipoprotein and its components by myeloperoxidase/H2O2/Cl- system

Oliveira

Brunetti

Khalil

2015

An. Acad. Bras. Ciênc.

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In this study, the effect of nicotine on the LDL oxidation by the MPO/H 2 O 2 /Cl -system and the effect of HOCl on LDL and some of its components, such as methyl linoleate, vitamin E and the amino acid tryptophan were explored. Nicotine, in micromolar concentrations, enhanced the tryptophan oxidation, either present in LDL or free, in solution. Nicotine also decreased the formation of conjugated dienes and oxygen consumption in a methyl linoleate / HOCl system, and there was evidence to suggest an increase in chlorohydrin formation. Acceleration of the vitamin E oxidation by HOCl was also observed in the presence of nicotine. These data show that the interaction of nicotine and HOCl can promote significant biochemical modifications in LDL particle and some of its components involved in the pathogenesis of cardiovascular and other diseases.

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Human Low Density Lipoprotein as a Target of Hypochlorite Generated by Myeloperoxidase

Cited by 52 publications

References 27 publications

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

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

Oxidation of LDL by Myeloperoxidase and Reactive Nitrogen Species

Nicotine-enhanced oxidation of low-density lipoprotein and its components by myeloperoxidase/H2O2/Cl- system

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