Mildly oxidised LDL induces more macrophage death than moderately oxidised LDL: roles of peroxidation, lipoprotein-associated phospholipase A2 and PPARgamma.
Death of macrophages and smooth muscle cells (SMC) can lead to progression of atherosclerosis. Mildly oxidised low-density lipoprotein (mildly-oxLDL) induced more overall death and apoptosis than moderately oxidised LDL, in human monocyte-macrophages (HMM). Mildly-oxLDL also induced more overall death in human SMC than did moderately-oxLDL. Mildly-oxLDL contained more hydroperoxides, but less oxysterol, malondialdehyde and negative charge than moderately-oxLDL. Specific inhibition of lipoprotein-associated phospholipase A(2) (by SB222657) diminished death induction in HMM by both oxLDL types. Peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist (GW9662) and agonist (ciglitazone) experiments suggested that non-hydrolysed, oxidised phospholipids in oxLDL activate PPARgamma as a cellular defence mechanism. These results may be relevant to LDL oxidation within atherosclerotic plaques and may suggest strategies for combating atherosclerosis progression.
Carpenter
Keri L H
KL
University of Cambridge, Department of Pathology, UK. klc1000@wbic.cam.ac.uk
Challis
Iain R
IR
Arends
Mark J
MJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects*; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D008077:Lipoproteins, LDL; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase