This Article Full Text Full Text (PDF) All Versions of this Article: 110/15/2143    most recent 01.CIR.0000143830.59419.73v1 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sanada, S. Articles by Kitakaze, M. Search for Related Content PubMed PubMed Citation Articles by Sanada, S. Articles by Kitakaze, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy Heart Attack Hazardous Substances DB THEOPHYLLINE Related Collections Animal models of human disease Cell signalling/signal transduction Ischemic biology - basic studies

(Circulation. 2004;110:2143-2149.)
© 2004 American Heart Association, Inc.

Congenital Heart Disease

Optimal Windows of Statin Use for Immediate Infarct Limitation

5'-Nucleotidase as Another Downstream Molecule of Phosphatidylinositol 3-Kinase

Shoji Sanada, MD, PhD; Hiroshi Asanuma, MD, PhD; Tetsuo Minamino, MD, PhD; Koichi Node, MD, PhD; Seiji Takashima, MD, PhD; Hiroko Okuda, , PhD; Yoshiro Shinozaki, MD, PhD; Akiko Ogai, PhD; Masashi Fujita, MD; Akio Hirata, MD; Jiyoong Kim, MD; Yoshihiro Asano, MD, PhD; Hidezo Mori, MD, PhD; Hitonobu Tomoike, MD, PhD; Soichiro Kitamura, MD, PhD; Masatsugu Hori, MD, PhD; Masafumi Kitakaze, MD, PhD

From the Department of Internal Medicine and Therapeutics (S.S., H.A., T.M., S.T., H.O., M.F., A.H., Y.A., M.H.), Osaka University Graduate School of Medicine, Suita; the Department of Cardiovascular and Renal Medicine (K.N.), Saga University Faculty of Medicine, Saga; the Department of Physiological Science (Y.S.), Tokai University School of Medicine, Isehara; and the Cardiovascular Division of Medicine (A.O., J.K., H.M., H.T., S.K., M.K.), National Cardiovascular Center, Suita, Japan.

Correspondence to Masafumi Kitakaze, MD, PhD, Director, Cardiovascular Division of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, 565-8565 Japan. E-mail kitakaze{at}zf6.so-net.ne.jp

Received March 26, 2004; revision received May 4, 2004; accepted May 7, 2004.

Background— Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model.

Methods and Results— Dogs were subjected to coronary occlusion (90 minutes) and reperfusion (6 hours) immediately after injection of pravastatin (0.2, 2, or 10 mg/kg), pitavastatin (0.01, 0.1, or 0.5 mg/kg), or cerivastatin (0.5, 5, or 50 µg/kg). Then myocardial phosphatidylinositol 3-kinase (PI3-K) and 5'-nucleotidase activities were measured, as well as infarct size. After 15 minutes of reperfusion, pravastatin caused dose-dependent activation of Akt and ecto-5'-nucleotidase in the ischemic zone, and the effect was significant at higher doses. Pitavastatin also significantly increased these activities, and its optimal dose was within the clinical range, whereas cerivastatin caused activation at the lowest dose tested. In all cases, both Akt and ecto-5'-nucleotidase showed activation in parallel, and this activation was completely abolished by wortmannin, a PI3-K inhibitor. The magnitude of the infarct-limiting effect paralleled the increase in Akt and ecto-5'-nucleotidase activity and was blunted by administration of wortmannin, ,ß-methyleneadenosine-5'-diphosphate, or 8-sulfophenyltheophylline during reperfusion. Both collateral flow and the area at risk were comparable for all groups.

Conclusions— Activation of ecto-5'-nucleotidase after ischemia by PI3-K activation may be crucial for immediate infarct-size limitation by statins. There seems to be an optimal dose for each statin that is independent of its clinical cholesterol-lowering effect.

Key Words: statins • myocardial infarction • adenosine • enzymes • phosphates

This article has been cited by other articles:

				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. 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]

				S. Jalkanen and M. Salmi VAP-1 and CD73, Endothelial Cell Surface Enzymes in Leukocyte Extravasation Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 18 - 26. [Abstract] [Full Text] [PDF]

				L. Zhang, Z. G. Zhang, X. S. Liu, A. Hozeska-Solgot, and M. Chopp The PI3K/Akt Pathway Mediates the Neuroprotective Effect of Atorvastatin in Extending Thrombolytic Therapy After Embolic Stroke in the Rat Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2470 - 2475. [Abstract] [Full Text] [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]

				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]

				M. Fujita, H. Asanuma, A. Hirata, M. Wakeno, H. Takahama, H. Sasaki, J. Kim, S. Takashima, O. Tsukamoto, T. Minamino, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H2004 - H2008. [Abstract] [Full Text] [PDF]

				Y. Ye, Y. Lin, S. Atar, M.-H. Huang, J. R. Perez-Polo, B. F. Uretsky, and Y. Birnbaum Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1158 - H1169. [Abstract] [Full Text] [PDF]

				A. Zernecke, K. Bidzhekov, B. Ozuyaman, L. Fraemohs, E. A. Liehn, J. M. Luscher-Firzlaff, B. Luscher, J. Schrader, and C. Weber CD73/Ecto-5'-Nucleotidase Protects Against Vascular Inflammation and Neointima Formation Circulation, May 2, 2006; 113(17): 2120 - 2127. [Abstract] [Full Text] [PDF]

				S. Atar, Y. Ye, Y. Lin, S. Y. Freeberg, S. P. Nishi, S. Rosanio, M.-H. Huang, B. F. Uretsky, J. R. Perez-Polo, and Y. Birnbaum Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1960 - H1968. [Abstract] [Full Text] [PDF]

				J. Herrmann Peri-procedural myocardial injury: 2005 update Eur. Heart J., December 1, 2005; 26(23): 2493 - 2519. [Abstract] [Full Text] [PDF]

				R. Schulz Pleiotropic effects of statins: Acutely good, but chronically bad? J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1292 - 1294. [Full Text] [PDF]