Lipoprotein associated phospholipase A2 inhibition reduces generation of oxidized fatty acids: Lp-LPA2 reduces oxidized fatty acids.
OBJECTIVE
Lipoprotein associated phospholipase A(2) (Lp-PLA(2)) is an emerging cardiovascular risk marker. After low-density lipoprotein (LDL) oxidation, Lp-PLA(2) generates oxidized nonesterified fatty acids and lysophosphatidylcholine, both of which have demonstrated proinflammatory and proapoptotic activities. Through the use of a selective inhibitor of Lp-PLA(2) (SB-677116), we investigated whether Lp-PLA(2) participates in the ex vivo generation of oxidized fatty acids (ox-FA).


METHODS
Due to the higher correlation between Lp-PLA(2) activity and small LDL particles, we investigated the effects of a selective Lp-PLA(2) inhibition on production of ox-FA in metabolic syndrome subjects with small LDL size <20.5 nm. Whole blood samples were incubated with vehicle (0 microM) or SB-677116 for 6 h at two different concentrations (0.3, 3.0 microM) to determine the effects of inhibitor on Lp-PLA(2) activity, the formation of oxidized esterified and nonesterified hydroxy-fatty acid (OH-FA) or ox-FA in 24 subjects.


RESULTS
Whole blood incubation with Lp-PLA(2) inhibitor (0.3, 3.0 microM) reduced multiple C-18 OH-FA subclasses (p < 0.05 versus control). For the highly redox-sensitive 9-OH-FA, there was a concentration-dependent reduction in Lp-PLA(2) activity and 9-OH-FA (p (trend) = 0.0016)


CONCLUSIONS
In conclusion, selective inhibition of Lp-PLA(2) reduced levels of OH-FA generated in whole blood of metabolic syndrome patients. These novel findings suggest that Lp-PLA(2) inhibition may attenuate some noxious downstream effects of lipid peroxidation that potentially include inflammatory responses.
Rosenson
Robert S
RS
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA. rrosenso@umich.edu
Vracar-Grabar
Marina
M
Helenowski
Irene
I
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000503:physiopathology*; D008875:Middle Aged; D010084:Oxidation-Reduction; D010865:Pilot Projects
D005230:Fatty Acids, Nonesterified; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase