Paraoxonase-1 reduces monocyte chemotaxis and adhesion to endothelial cells due to oxidation of palmitoyl, linoleoyl glycerophosphorylcholine.

Abstract

High-density lipoprotein (HDL) is postulated to protect against the development of atherosclerosis, in part, by inhibiting the oxidation of low density lipoprotein (LDL) in the sub-endothelial space and thus inhibiting activation of the endothelium. The HDL-associated enzyme, paraoxonase-1, is proposed to be a major protective factor. However, HDL is also prone to oxidation when exposed to peroxynitrite and may therefore, once oxidized, have properties similar to oxidized LDL. We exposed human HDL to the peroxynitrite donor 3-morpholinosydnonimine and incubated oxidized HDL with human umbilical vein endothelial cells (HUVECs). Oxidized HDL increased monocyte binding (P<0.001) and enhanced chemotaxis (P<0.001). The major oxidized phospholipids were 1-palmitoyl (stearoyl)-2-[9-oxo]nanoyl(azelaoyl)-sn-glycero-phosphocholine, derived from linoleate-containing phosphatidylcholines, and 1-palmitoyl(stearoyl)-2-[5-oxo]valeroyl(glutaroyl)-sn-glycero-phosphocholine, derived from arachidonate-containing phosphatidylcholines. Incubation of HUVECs with synthetically prepared 1-palmitoyl-2-[9-oxo]nanoyl(azelaoyl)-sn-glycero-phosphocholine, or 1-palmitoyl-2-[5-oxo]valeroyl(glutaroyl)-sn-glycero-phosphocholine increased binding of monocytes (P<0.001) and chemotaxis (P<0.001). Purified paraoxonase-1 reduced monocyte adhesion and chemotaxis (P<0.001). (i) HDL can be a source of oxidatively-derived bioactive phospholipids; (ii) the fragmented phospholipids with a 9-carbon aldehyde or acid are as effective as a 5-carbon aldehyde or acid at inducing monocyte adhesion and chemotaxis; and (iii) paraoxonase-1 is effective at reducing the activity of these phospholipid oxidation products.