title: Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood. Relevance to atherogenesis caused by hemodialysis.
abstract: Human blood contains a form of minimally modified low density lipoprotein (LDL), termed LDL-, whose origin remains unknown. Exploring the mechanism of formation, we found that LDL- can be produced in plasma in the absence of oxygen following LDL incubation with oxidized hemoglobin species. A high degree of apolipoprotein B100 modification results from covalent association of hemoglobin with LDL involving dityrosine formation but not due to the malonaldehyde epitope formation. This was evidenced by the cross-reactivity of oxidized LDL with antibodies against hemoglobin that was accompanied by a 60-fold increase in dityrosine levels. In this study we found significantly higher LDL- levels in the blood of hemodialysis patients, perhaps contributing to their greatly increased risk of atherosclerosis. The mechanism of LDL- formation was studied during ex vivo blood circulation using a model system resembling clinical hemodialysis in terms of the induction of inflammatory responses. This circulation increased free hemoglobin and LDL- levels compared with non-circulated blood without appreciable lipid peroxidation. Pronounced increases in LDL- were found also during circulation of plasma supplemented with nanomolar hemoglobin levels. The increase in dityrosine content and presence of heme in LDL after blood circulation suggest that LDL is modified, in part, by hemoglobin-LDL conjugates containing heme. Thus, hemoglobin-mediated reactions leading to LDL oxidation in plasma can account for high LDL- levels in hemodialysis patients.
authors.affiliation: Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: O
authors.initials: O
authors.lastname: Ziouzenkova
authors.forename: L
authors.initials: L
authors.lastname: Asatryan
authors.forename: M
authors.initials: M
authors.lastname: Akmal
authors.forename: C
authors.initials: C
authors.lastname: Tetta
authors.forename: M L
authors.initials: ML
authors.lastname: Wratten
authors.forename: G
authors.initials: G
authors.lastname: Loseto-Wich
authors.forename: G
authors.initials: G
authors.lastname: Jürgens
authors.forename: J
authors.initials: J
authors.lastname: Heinecke
authors.forename: A
authors.initials: A
authors.lastname: Sevanian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood*; D001161:Arteriosclerosis / Q000209:etiology*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications / Q000628:therapy; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; D006435:Renal Dialysis / Q000009:adverse effects*
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D006454:Hemoglobins; D008077:Lipoproteins, LDL; D008315:Malondialdehyde