Impact of atorvastatin treatment on platelet-activating factor acetylhydrolase and 15-F_2trans-isoprostane in hypercholesterolaemic patients

摘要

What is already known about this subject ? Isoprostanes are the product of free radical oxidation of arachidonic acid bound to phospholipids. ? Their hydrolysis from phospholipids is presumably catalysed by phospholipases A ₂ . ? Atorvastatin reduces protein concentrations of secretory PLA ₂ s and concentrations of LDL, with which PAF-AH (group VII phospholipase) is associated. What this study adds ? Atorvastatin affects PAF-AH activity and this effect is strongly associated with its lipid-lowering effect, but it has no effect on groups IIA and V PLA ₂ s' activity. ? Thus, PAF-AH is no independent risk factor of cardiovascular diseases. ? Moreover, a role of PAF-AH in the liberation of 15-F _2t -isoP from phospholipids is excluded. Aims Isoprostanes are the product of free radical oxidation of arachidonic acid, whose hydrolysis from phospholipids is presumably catalysed by phospholipases A ₂ (PLA ₂ s) such as group IIA or V PLA ₂ s, or group VII PLA ₂ [platelet-activating factor acetylhydrolase (PAF-AH), lipoprotein-associated phospholipase]. Atorvastatin reduces concentrations of low-density lipoprotein (LDL), with which PAF-AH is associated, and PLA ₂ s' protein concentrations. We investigated the effect of atorvastatin on PLA ₂ s and PAF-AH activity and the urinary excretion of 15-F _2trans -isoprostane (15-F _2t -IsoP, 8-iso-PGF _2α , iPF _2α -III). Methods Twenty-four hypercholesterolaemic individuals naive to lipid-lowering therapy were randomized to atorvastatin 40 mg or placebo for 6 weeks. The 15-F _2t -isoP urinary excretion (gas chromatography/mass spectrometry), PAF-AH and group IIA and V PLA ₂ activities (photometry) were assessed at baseline and end-point. Results At end-point, 15-F _2t -isoP urinary excretion concentrations as well as PLA ₂ s' activity were unchanged under atorvastatin (mean change 0.21 ± 1.79 ng h ^?1 , 95% confidence interval ?0.92, 1.35 and 0.33 ± 0.94 nmol min ^?1 ml ^?1 , ?0.27, 0.93) and under placebo (mean change 0.69 ± 1.69 ng h ^?1 , ?0.52, 1.90 and 1.29 ± 2.16 nmol min ^?1 ml ^?1 , ?0.25, 2.84). Atorvastatin treatment decreased total ( P ?1 ml ^?1 , ?6.51, ?4.03, P ?1 ml ^?1 , 0.15, 2.20), and the change in PAF-AH activity was correlated with that in total ( P = 0.03) and LDL-cholesterol ( P = 0.03). Conclusion Our results show a lowering effect of atorvastatin on PAF-AH activity associated with its lipid-lowering effect and exclude a key role of PAF-AH in the liberation of 15-F _2t -isoP from phospholipids.