Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidised LDL on human monocyte-macrophages.
The death of macrophages contributes to atheroma formation. Oxidation renders low-density lipoprotein (LDL) cytotoxic to human monocyte-macrophages. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also termed platelet-activating factor acetylhydrolase, hydrolyses oxidised phospholipids. Inhibition of Lp-PLA2 by diisopropyl fluorophosphate or Pefabloc (broad-spectrum serine esterase/protease inhibitors), or SB222657 (a specific inhibitor of Lp-PLA2) 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 apoptosis-inducing effects of oxidised LDL on macrophages.
Carpenter
K L
KL
Department of Pathology, University of Cambridge, UK. klhc@mole.bio.cam.ac.uk
Dennis
I F
IF
Challis
I R
IR
Osborn
D P
DP
Macphee
C H
CH
Leake
D S
DS
Arends
M J
MJ
Mitchinson
M J
MJ
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001384:Azetidines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007531:Isoflurophate / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000502:physiology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D013450:Sulfones / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology
D001384:Azetidines; D004791:Enzyme Inhibitors; D008074:Lipoproteins; D008077:Lipoproteins, LDL; C118636:SB 222657; D013450:Sulfones; D013454:Sulfoxides; C099252:oxidized low density lipoprotein; D007531:Isoflurophate; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D010741:Phospholipases A; D054467:Phospholipases A2