Phospholipid hydrolysis of mildly oxidized LDL reduces their cytotoxicity to cultured endothelial cells. Potential protective role against atherogenesis.
Oxidized low density lipoproteins (LDL) are cytotoxic to cultured endothelial cells and thereby are potentially involved in endothelial cell injury and atherogenesis. Oxidized phospholipids of oxLDL undergo spontaneous hydrolysis (PL-hydrolysis) by LDL-associated phospholipase A2 (PLA2) activities. The present study aimed to investigate whether hydrolysis of oxidized phospholipids contained in mildly oxLDL could influence their cytotoxicity to cultured endothelial cells. PL-hydrolysis (spontaneous or mediated by exogenous PLA2) of mildly oxLDL elicited a significant reduction of their cytotoxicity to cultured endothelial cells. The reduced cytotoxicity of PL-hydrolysed oxLDL was not due to their reduced uptake by cells, but rather to their reduced content of oxidation products which are liberated by PL-hydrolysis and released (at least the more polar compounds) in the aqueous phase, as shown by ultrafiltration experiments. Oxidation products released in the aqueous phase were not or only slightly cytotoxic to endothelial cells, probably because a selective uptake of non oxidized fatty acids as shown by studies of uptake of oxidized and non oxidized [1-14C]linoleic acid. These data suggest that during PL-hydrolysis of mildly oxLDL, (i) oxidized phospholipids are hydrolysed; (ii) oxidation products liberated from oxLDL particles are released (at least in part) to the aqueous phase; (iii) the cytotoxicity of oxLDL to endothelial cells is reduced, probably because oxidized free fatty acids (released by PL-hydrolysis towards the aqueous phase) are not taken up by the cells. Finally, the possibility of a favourable role of PL-hydrolysis of oxLDL against atherogenesis is discussed.
Schmitt
A
A
Department of Biochemistry, Faculty of Medicine in Rangueil, University Paul Sabatier, CHU Rangueil, Toulouse, France.
Nègre-Salvayre
A
A
Troly
M
M
Valdiguié
P
P
Salvayre
R
R
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D002250:Carbon Radioisotopes; D002417:Cattle; D002460:Cell Line / Q000187:drug effects; D003603:Cytotoxins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006868:Hydrolysis; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry*
D002250:Carbon Radioisotopes; D003603:Cytotoxins; D008041:Linoleic Acids; D008077:Lipoproteins, LDL; D010743:Phospholipids; D019787:Linoleic Acid