Published Online
on August 14, 2006

A more recent version of this article appeared on August 29, 2006

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Submitted on April 3, 2006
Revised on June 9, 2006
Accepted on June 22, 2006

Augmentation of Myocardial Production of 15-Epi-Lipoxin-A₄ by Pioglitazone and Atorvastatin in the Rat

Yochai Birnbaum MD^*, Yumei Ye MD, Yu Lin BSc, Sheldon Y. Freeberg MD, Shawn P. Nishi MD, Juan D. Martinez MD, Ming-He Huang MD, Barry F. Uretsky MD, and Jose R. Perez-Polo PhD

From the Division of Cardiology (Y.B., Y.Y., Y.L., M.-H.H., B.F.U.), Department of Internal Medicine (S.Y.F., S.P.N., J.D.M.), and Department of Biochemistry and Molecular Biology (J.R.P.-P.), University of Texas Medical Branch, Galveston.

^* To whom correspondence should be addressed. E-mail: yobirnba{at}utmb.edu.

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^-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.

Key words: aspirin • diabetes mellitus • hypercholesterolemia • inflammation • prostaglandins

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