Generation in Human Plasma of Misfolded, Aggregation-Prone Electronegative Low Density Lipoprotein

Abstract

Human plasma contains small amounts of a low density lipoprotein in which apoprotein is misfolded. Originally identified and isolated by means of anion-exchange chromatography, this component was subsequently described as electronegative low density lipoprotein (LDL)(-), with increased concentrations associated with elevated cardiovascular disease risk. It has been recognized recently as the trigger of LDL amyloidogenesis, which produces aggregates similar to subendothelial droplets observed in vivo in early atherogenesis. Although LDL(-) has been produced in vitro through various manipulations, the mechanisms involved in its generation in vivo remain obscure. By using a more physiological model, we demonstrate spontaneous, sustained and noticeable production of LDL(-) during incubation of unprocessed human plasma at 37 degrees C. In addition to a higher fraction of amyloidogenic LDL(-), LDL purified from incubated plasma contains an increased level of lysophospholipids and free fatty acids; analysis of LDL lipids packing shows their loosening. As a result, during plasma incubation, lipid destabilization and protein misfolding take place, and aggregation-prone particles are generated. All these phenomena can be prevented by inhibiting calcium-dependent secretory phospholipases A2. Our plasma incubation model, without removal of reaction products, effectively shows a lipid-protein interplay in LDL, where lipid destabilization after lipolysis threatens the apoprotein's structure, which misfolds and becomes aggregation-prone.

Effects of phospholipase A2 and its products on structural stability of human LDL: relevance to formation of LDL-derived lipid droplets

“…3 ). This result is consistent with the far-UV CD spectra of hydrolyzed LDL reported by Greco et al ( 11 ). Furthermore, LDL heating also leads to preferential unfolding of the b -sheet structure in apoB (supplementary Fig.…”

Circulating Atherogenic Multiple-Modified Low-Density Lipoprotein: Pathophysiology and Clinical Applications

“…Subendothelial cells Advances in Lipoprotein Researchtake up LDL(−) via scavenger receptors, which leads to saturation of their cytoplasm with lipid deposits and results in foam cell formation. Autoantibodies to LDL(−) can contribute to the development of atherosclerosis as well [47]. LDL(−) is cytotoxic to endothelial cells, inducing apoptosis and provoking production of inflammatory molecules such as IL-8, VCAM-1, and MCP-1 [47].…”

“…Autoantibodies to LDL(−) can contribute to the development of atherosclerosis as well [47]. LDL(−) is cytotoxic to endothelial cells, inducing apoptosis and provoking production of inflammatory molecules such as IL-8, VCAM-1, and MCP-1 [47]. Therefore, LDL(−) was demonstrated to be pro-atherogenic and pro-inflammatory.…”

Atherogenic modification of low-density lipoproteins

“…Из-за связывания с протеогликанами происходит удерживание ЛНП(-) в субэндотелиальной интиме. ЛНП(-) проявляют цитотоксический эффект на эндотелиальных клетках, вызывая апоптоз и продукцию провоспалительных молекул, таких как ИЛ-8, MCP-1 и VCAM-1 [53][54][55]. Таким образом, накопленные данные свидетельствуют о проатерогенных и провоспалительных свойствах ЛНП(-).…”