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(Circulation. 2006;114:929-935.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Yochai Birnbaum, MD, Division of Cardiology, University of Texas Medical Branch, 5106 John Sealy Annex, 301 University Blvd, Galveston, Texas 77555-0553. E-mail yobirnba{at}utmb.edu

Received April 3, 2006; revision received June 9, 2006; accepted June 22, 2006.

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.

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