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-A4 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·d; ATV 2, 5, or 10 mg·kg·d; or PIO 10 mg·kg·d+ATV 10 mg·kg·d. In experiment 2, rats received water; PIO 10 mg·kg·d+ATV 10 mg·kg·d; 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·d 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.