Propietats aterogèniques de l'LDL electronegativa: inducció de l'expressió de citoquines, activitats enzimàtiques associades i unió a proteoglicans

Abstract

Electronegative LDL (LDL(-)) is a modified fraction of LDL present in circulation. Growing evidence suggests an atherogenic role. LDL(-) proportion is increased in diseases with high cardiovascular risk, as familial hypercholesterolemia or diabetes mellitus. Furthermore, it presents inflammatory properties, high susceptibility to aggregation and decreased LDL receptor affinity. In the current thesis some atherogenic properties of this modified particle have been studied, specifically, the following points have been evaluated: 1) Inflammatory properties. LDL(-) induced increased expression of cytokines (IL-6), chemokines (IL-8, MCP-1 and GRO) and grown factors (GM-CSF) on venous and arterial endothelial cells, monocytes and lymphocytes. Arterial endothelial cells produced a high amount of cytokines and, moreover, they also stimulated PDGF-B. On the other hand, monocytes and lymphocytes also expressed the anti-inflammatory cytokine IL-10, who decreased the secretion of the other pro-inflammatory cytokines, thereby counteracting the inflammatory response. 2) Phospholipase C-like phospholipolytic activity associated to LDL(-). Novel enzymatic activities present on LDL(-) that hydrolyze choline-containing phospholipids have been described. These activities have been involved in increased susceptibility to aggregation. A role for apoE, apoC-III and PAF-AH has been ruled out and our results suggest that apoB-100 could be involved. However, the exact origin remains unknown. 3) Binding to proteoglycans from the extracellular matrix. A subfraction of LDL(-) presented increased binding to proteoglycans isolated from human artery. This subfraction has increased aggregation and phospholipolytic activity. Both properties are related, suggesting that phospholipolytic activity promotes aggregation and favours binding to proteoglycans. In summary, LDL(-) is a potentially atherogenic particle since promotes inflammatory molecules release in several cell types and its increased aggregation and binding to proteoglycans suggests increased subendothelial retention.

Date of Award	1 Apr 2009
Original language	Undefined/Unknown
Supervisor	Sonia Benítez González (Director), José Luis Sánchez Quesada (Director) & Jorge Ordóñez Llanos (Director)