HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1158    most recent 00096.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Ye, Y. Articles by Birnbaum, Y. Search for Related Content PubMed PubMed Citation Articles by Ye, Y. Articles by Birnbaum, Y.

Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions

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

This article has been cited by other articles:

				M.-H. Huang, V. Nguyen, Y. Wu, S. Rastogi, C. Y. Lui, Y. Birnbaum, H.-Q. Wang, D. L. Ware, M. Chauhan, N. Garg, et al. Reducing ischaemia/reperfusion injury through {delta}-opioid-regulated intrinsic cardiac adrenergic cells: adrenopeptidergic co-signalling Cardiovasc Res, July 31, 2009; (2009) cvp233v3. [Abstract] [Full Text] [PDF]

				S. Yasuda, H. Kobayashi, M. Iwasa, I. Kawamura, S. Sumi, B. Narentuoya, T. Yamaki, H. Ushikoshi, K. Nishigaki, K. Nagashima, et al. Antidiabetic drug pioglitazone protects the heart via activation of PPAR-{gamma} receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1558 - H1565. [Abstract] [Full Text] [PDF]

				Y. Ye, Y. Lin, S. Manickavasagam, J. R. Perez-Polo, B. C. Tieu, and Y. Birnbaum Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2436 - H2446. [Abstract] [Full Text] [PDF]

				L. Gao, W. Wang, and I. H. Zucker Simvastatin Inhibits Central Sympathetic Outflow in Heart Failure by a Nitric-Oxide Synthase Mechanism J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 278 - 285. [Abstract] [Full Text] [PDF]

				Y. Ye, J. D. Martinez, R. J. Perez-Polo, Y. Lin, B. F. Uretsky, and Y. Birnbaum The role of eNOS, iNOS, and NF-{kappa}B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H343 - H351. [Abstract] [Full Text] [PDF]

				Y.-J. Yang, H.-Y. Qian, J. Huang, Y.-J. Geng, R.-L. Gao, K.-F. Dou, G.-S. Yang, J.-J. Li, R. Shen, Z.-X. He, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts Eur. Heart J., June 2, 2008; 29(12): 1578 - 1590. [Abstract] [Full Text] [PDF]

				Y. Birnbaum, Y. Lin, Y. Ye, R. Merla, J. R. Perez-Polo, and B. F. Uretsky Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2008; 13(1): 72 - 79. [Abstract] [PDF]

				E. Erdmann Review: Statin plus thiazolidinedione use in patients with diabetes at high cardiovascular risk The British Journal of Diabetes & Vascular Disease, September 1, 2007; 7(5): 211 - 216. [Abstract] [PDF]

				R. Merla, Y. Ye, Y. Lin, S. Manickavasagam, M.-H. Huang, R. J. Perez-Polo, B. F. Uretsky, and Y. Birnbaum The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1918 - H1928. [Abstract] [Full Text] [PDF]

				M.-H. Huang, H.-Q. Wang, W. R. Roeske, Y. Birnbaum, Y. Wu, N.-P. Yang, Y. Lin, Y. Ye, D. J. McAdoo, M. G. Hughes, et al. Mediating {delta}-opioid-initiated heart protection via the beta2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H376 - H384. [Abstract] [Full Text] [PDF]

				Y. Ye, Y. Lin, R. Perez-Polo, M.-H. Huang, M. G. Hughes, D. J. McAdoo, S. Manickavasagam, B. F. Uretsky, and Y. Birnbaum Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H813 - H818. [Abstract] [Full Text] [PDF]

				G. Salinas, U. C. Rangasetty, B. F. Uretsky, and Y. Birnbaum The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 98 - 111. [Abstract] [PDF]

				Y. Birnbaum, Y. Lin, Y. Ye, J. D. Martinez, M.-H. Huang, C. Y. Lui, J. R Perez-Polo, and B. F. Uretsky Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2891 - H2897. [Abstract] [Full Text] [PDF]