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(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

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