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CARDIOVASCULAR
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.T., M.H., J.K., K.F.); and Drug Research Department, Toa Eiyo Ltd., Fukushima, Japan (K.A.)
In a rat model of myocardial ischemic infarction, sodium orthovanadate rescued cells from ischemia/reperfusion injuries. Rats underwent 30 min of myocardial ischemia by occluding the left coronary artery followed by 24 h of reperfusion. Post-treatment with orthovanadate reduced infarct size in a dose-dependent manner. Orthovanadate treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. The cytoprotective action of orthovanadate treatment was closely associated with inhibition of fodrin breakdown. Since orthovanadate is a potent inhibitor for protein tyrosine phosphatases, thereby activating tyrosine kinases and phosphatidylinositol 3-kinase (PI3K) pathways, we investigated activities of protein kinase B (Akt), a downstream target of PI3K in cardiomyocytes. Orthovanadate-induced cytoprotection was associated with partial restoration of reduced Akt activity following myocardial infarction. Restoration of Akt activity by orthovanadate treatment correlated positively with increased phosphorylation of glycogen synthase kinase-3
and Bad in cardiomyocytes. Furthermore, orthovanadate treatment inhibited caspase-3 activation induced by ischemia. Taken together, orthovanadate post-treatment rescued cardiomyocytes from ischemia/reperfusion injuries via Akt activation and inhibition of fodrin breakdown, thereby inhibiting apoptosis.
Address correspondence to: Dr. Kohji Fukunaga, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan. E-mail: fukunaga{at}mail.pharm.tohoku.ac.jp
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