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Am J Physiol Heart Circ Physiol 291: H1158-H1169, 2006. First published April 7, 2006; doi:10.1152/ajpheart.00096.2006
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Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions

Yumei Ye,1 Yu Lin,1 Shaul Atar,1 Ming-He Huang,1 Jose R. Perez-Polo,2 Barry F. Uretsky,1 and Yochai Birnbaum1

1Division of Cardiology and 2Department of Biochemistry and Molecular Genetics, University of Texas Medical Branch, Galveston, Texas

Submitted 23 January 2006 ; accepted in final form 28 March 2006

We assessed 1) whether pretreatment before ischemia with pioglitazone (Pio) limits infarct size (IS) and whether this protective effect is due to nitric oxide synthase (NOS) and/or prostaglandin production, as has been shown for atorvastatin (ATV); and 2) whether Pio and ATV have synergistic effects on myocardial protection. Sprague-Dawley rats received oral ATV (10 mg·kg–1·day–1), Pio (10 mg·kg–1·day–1), their combination (Pio + ATV), or water alone for 3 days. Additional rats received Pio (10 mg·kg–1·day–1) for 3 days and intravenous SC-58125 [a cyclooxygenase-2 (COX-2) inhibitor] or SC-560 (a COX-1 inhibitor) 15 min before ischemia. Rats underwent 30 min of myocardial ischemia and 4 h of reperfusion, or hearts were harvested for analysis. IS in the Pio and in the ATV groups was significantly smaller than in the sham-treated group. IS in the Pio + ATV group was smaller than in all other groups (P < 0.001 vs. each group). The protective effect of Pio was abrogated by SC-58125 but not by SC-560. Pio, ATV, and Pio + ATV increased the expression and activity of cytosolic phospholipase A2 (cPLA2) and COX-2. ATV increased phosphorylated-Akt, phosphorylated-endothelial NOS (P-eNOS), inducible NOS, and COX-2 levels. In contrast, Pio caused an insignificant increase in myocardial levels of phosphorylated-Akt but did not change P-eNOS and iNOS expression. In conclusion, the IS-limiting effects of Pio and ATV involve COX-2. However, the upstream steps differ. ATV induced eNOS phosphorylation and iNOS, cPLA2, and COX-2 expression, whereas Pio induced mainly the expression and activity of cPLA2. The effects of Pio and ATV were additive.

infarct size; thiazolidinediones; statins; cyclooxygenase-2; cytosolic phospholipase A2; nitric oxide synthase; protein kinase Akt; phosphatase and tensin homologue deleted on chromosome 10, anti-Src homology 2-containing inositol phosphatase-2


Address for reprint requests and other correspondence: Y. Birnbaum, Division of Cardiology, Univ. of Texas Medical Branch, 5.106 John Sealy Annex, 301 Univ. Blvd., Galveston, Texas 77555-0553 (e-mail: yobirnba{at}utmb.edu)




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