Lipoprotein associated phospholipase A2 inhibition reduces generation of oxidized fatty acids: Lp-LPA2 reduces oxidized fatty acids

Cardiovasc Drugs Ther. 2008 Feb;22(1):55-8. doi: 10.1007/s10557-008-6080-4. Epub 2008 Jan 23.

Abstract

Purpose: 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.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Fatty Acids, Nonesterified / metabolism*
  • Female
  • Humans
  • In Vitro Techniques
  • Lipid Peroxidation / drug effects
  • Lipoproteins, LDL / metabolism
  • Male
  • Metabolic Syndrome / physiopathology*
  • Middle Aged
  • Oxidation-Reduction
  • Pilot Projects

Substances

  • Fatty Acids, Nonesterified
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase