Inhibition of lipoprotein‐associated phospholipase A₂ diminishes the death‐inducing effects of oxidised LDL on human monocyte‐macrophages

Abstract

The death of macrophages contributes to atheroma formation. Oxidation renders low-density lipoprotein (LDL) cytotoxic to human monocyte-macrophages. Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), also termed platelet-activating factor acetylhydrolase, hydrolyses oxidised phospholipids. Inhibition of Lp-PLA 2 by diisopropyl fluorophosphate or Pefabloc (broad-spectrum serine esterase/protease inhibitors), or SB222657 (a specific inhibitor of Lp-PLA 2 ) did not prevent LDL oxidation, but diminished the ensuing toxicity and apoptosis induction when the LDL was oxidised, and inhibited the rise in lysophosphatidylcholine levels that occurred in the inhibitors' absence. Hydrolysis products of oxidised phospholipids thus account for over a third of the cytotoxic and apoptosisinducing effects of oxidised LDL on macrophages. ß

Platelet-Activating Factor Acetylhydrolase Is Mainly Associated With Electronegative Low-Density Lipoprotein Subfraction

“…4,5 The use of specific inhibitors also supports this possibility, because PAF-AH inhibition decreased monocyte chemotactic activity 3,23 and apoptosis 26 induced by "in vitro"-oxidized LDL and reduced atherosclerotic plaque development in a 3-month study in rabbits. 6 However, the putative proinflammatory role of PAF-AH should be considered with caution, because its anti-inflammatory role through the degradation of PAF and PAF-like lipids is well established.…”

“…Both LPC and NEFA are known inflammation mediators. LPC is chemotactic for monocytes, 3,25 induces apoptosis in endothelial and smooth muscle cells, 26 and increases monocyte chemotactic protein-1 expression in endothelial cells. 27 Oxidized NEFA is also a chemoattractant to monocytes.…”

Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein

“…These studies were conducted using modified KBr density gradients to improve resolution in the heavy density region (see "Experimental Procedures"). Panel A illustrates the density of fractions corresponding to all gradients shown in this figure. by oxidized LDL (40,41) and to reduce atherosclerotic lesion formation in Watanabe heritable hyperlipidemic rabbits (42). SB-480848 (Darapladib) is currently being tested in humans as a potential treatment for atherosclerosis (43).…”

New Markers of Inflammation and Endothelial Cell Activation

“…29 Implicated with oxLDL toxicity is lipoprotein-associated phospholipase A 2 , an enzyme that, when inhibited, reduces macrophage death. 30 The death of macrophage foam cells leads to lipid spillage, promoting further inflammation, while SMC death further reduces collagen synthesis and promotes fibrous cap thinning.…”