Augmentation of myocardial production of 15-epi-lipoxin-A4 by pioglitazone and atorvastatin in the rat

Background-Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A(4) and 15(R)-epi-lipoxin-A4 (15-epi-LXA4), both arachidonic acid products with strong antiinflammatory properties. Methods and Results-In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg (.) kg(-1 .) d(-1); ATV 2, 5, or 10 mg (.) kg(-1) (.) d(-1); or PIO 10 mg (.) kg(-1) (.) d(-1) + ATV 10 mg (.) kg(-1) (.) d(-1). In experiment 2, rats received water; PIO 10 mg (.) kg(-1) (.) d(-1) + ATV 10 mg . kg(-1) (.) d(-1); PIO + ATV and valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor; PIO + ATV and zileuton, a selective 5-lipoxygenase inhibitor; or zileuton alone. There were 4 rats in each group. Hearts were harvested and analyzed for myocardial lipoxin-A4 and 15-epi-LXA4 levels and for COX-2 and 5-lipoxygenase protein expression. ATV and PIO at 5 and 10 mg (.) kg(-1) (.) d(-1) significantly increased myocardial 15-epi-LXA4 levels compared with the sham-treated group (0.51 +/- 0.02 ng/ mg). Myocardial 15-epi-LXA4 were significantly higher in the PIO + ATV group (1.29 +/- 0.02 ng/ mg; P < 0.001 versus each other group). Both valdecoxib and zileuton abrogated the PIO + ATV increase in 15-epi-LXA4, whereas zileuton alone had no effect. PIO, ATV, and their combination resulted in a small increase in myocardial lipoxin-A4 levels, which was not statistically significant. ATV alone or in combination with PIO markedly augmented COX-2 expression. PIO had a much smaller effect on COX-2 expression. Myocardial expression of 5-lipoxygenase was not altered by PIO, ATV, or their combination. Conclusions-Both PIO and ATV increase myocardial levels of 15-epi-LXA4, a mediator with antiinflammatory properties. This finding may explain the antiinflammatory properties of both PIO and ATV.