LDL phospholipid hydrolysis produces modified electronegative particles with an unfolded apoB100 protein

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

Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, Los Angeles, CA 90033

Corresponding Author: 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 $beta$ -strand structural content and unfolding proportionate to the loss of $alpha$ -helical structure of apoB100 of LDL^- isolated from both native- and PLA₂-LDLs was demonstrated by circular dichrosim (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 due to exposure of otherwise inaccessible hydrophilic and hydrophobic domains arising from apoB100 unfolding. This was also demonstrated for plasma LDL^-. In contrast, PLA₂-LDL was more resistant to copper-mediated oxidation that was reversed upon adding 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 electronegative LDL that is facilitated by unfolding of apoB100.

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