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Journal of Lipid Research, Vol. 46, 115-122, January 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

LDL phospholipid hydrolysis produces modified electronegative particles with an unfolded apoB-100 protein

Liana Asatryan^1,*, Ryan T. Hamilton^*, J. Mario Isas, Juliana Hwang^*, Rakez Kayed and Alex Sevanian^*

^* Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, CA 90033
Department of Biochemistry and Molecular Biology, Keck School of Medicine, Zilkha Neurogenetic Institute, and Arnold and Mabel Beckman Macular Research Center, University of Southern California, Los Angeles, CA 90033
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697

¹ To whom correspondence should be addressed. e-mail: asatryan{at}usc.edu

Electronegative low density lipoprotein (LDL^–) formation that structurally resembles LDL^– isolated from plasma was evaluated after LDL treatment with snake venom phospholipase A₂ (PLA₂). PLA₂ treatment of LDL increased its electrophoretic mobility in proportion to the amount of LDL^– formed without evidence of lipid peroxidation. These changes dose-dependently correlated with the degree of phospholipid hydrolysis. Strong immunoreactivity of LDL^– subfraction from plasma and PLA₂-treated LDL (PLA₂-LDL) to amyloid oligomer-specific antibody was observed. Higher ß-strand structural content and unfolding proportionate to the loss of -helical structure of apolipoprotein B-100 (apoB-100) of LDL^– isolated from both native and PLA₂-LDLs was demonstrated by circular dichroism (CD) spectropolarimetry. These structural changes resembled the characteristics of some oxidatively modified LDLs and soluble oligomeric aggregates of amyloidogenic proteins. PLA₂-LDL was also more susceptible to nitration by peroxynitrite, likely because of exposure of otherwise inaccessible hydrophilic and hydrophobic domains arising from apoB-100 unfolding. This was also demonstrated for plasma LDL^–. In contrast, PLA₂-LDL was more resistant to copper-mediated oxidation that was reversed upon the addition of small amounts of unsaturated fatty acids.

The observed similarities between PLA₂-LDL^–-derived LDL^– and plasma LDL^– implicate a role for secretory PLA₂ in producing modified LDL^– that is facilitated by unfolding of apoB-100.

Abbreviations: Aß, amyloid ß; apoB-100, apolipoprotein B-100; CD, circular dichroism; LDL^–, electronegative low density lipoprotein; MDA, malondialdehyde; nLDL, normal LDL subfraction devoid of LDL^–; REM, relative electrophoretic mobility; sPLA₂, secretory phospholipase A₂; tLDL, total LDL

Supplementary key words apolipoprotein B-100 • atherogenic low density lipoprotein • lipid peroxidation • oxidation • nitrotyrosine • unsaturated fatty acids • ß-strand structures • protein structure • secretory phospholipase A₂

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