Increased PAFAH and oxidized lipids are associated with inflammation and atherosclerosis in hypercholesterolemic pigs.
OBJECTIVE
To study the association of PAF-acetyl hydrolase (PAFAH) activity with inflammation, oxidative stress, and atherosclerosis in hypercholesterolemic swine.


RESULTS
Cholesterol-rich diet feeding of miniature pigs was associated with an increase in PAFAH activity and an increase of the PAFAH to PON1 ratio. PLA2G7 RNA (coding for PAFAH) expression was increased in blood monocytes and plaque macrophages. Increased PAFAH activity was associated with higher plasma lysophosphatidylcholine and correlated with oxidized LDL. In THP1 monocytes and macrophages and in human blood-derived macrophages, oxidized LDL induced PLA2G7 RNA expression. Atherogenic diet feeding induced the accumulation of macrophages and oxidized LDL in the arterial wall leading to atherosclerosis. PAFAH activity correlated positively with plaque size and TNFalpha expression in plaque macrophages.


CONCLUSIONS
We demonstrated that an increase in PAFAH activity was associated with increased levels of lysophosphatidylcholine, oxidized LDL, and inflammation, resulting in accelerated atherosclerosis in hypercholesterolemic minipigs. The significant correlation between PLA2G7 RNA expression in plaque macrophages and plasma PAFAH activity suggests that the latter is a consequence, rather than a cause of macrophage accumulation. Our cell experiments suggest that oxidized LDL can induce PAFAH, resulting in accumulation of lysophosphatidylcholine that increases the inflammatory action of oxidized LDL.
Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Belgium.
Dieuwke
D
De Keyzer
Sonia-Athina
SA
Karabina
Wenhzong
W
Wei
Benjamine
B
Geeraert
Dominique
D
Stengel
Judit
J
Marsillach
Jordi
J
Camps
Paul
P
Holvoet
Ewa
E
Ninio
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D043303:Aryldialkylphosphatase / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004036:Diet, Atherogenic; D015870:Gene Expression; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
D012313:RNA; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D043303:Aryldialkylphosphatase