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Aims Icariin ( ICA), a flavonoid isolated from epimedii, has been reported to have potential protective effects on the cardiovascular system. This study is to investigate the effect and the underlying mechanisms of ICA on ischemia/reperfusion (I/R) injury. Methods Wister rat hearts were subjected to I/R using Langendorff perfusion system. Cardiac function, myocardial infarct size, lactate dehydrogenase ( LDH), and creatine kinase- MB ( CK- MB) activities in coronary effluent, and superoxide dismutase ( SOD) and malondialdehyde ( MDA) content in heart tissue and cardiomyocyte apoptosis were assayed. Results Compared with the I/R group, ICA treatment significantly improved cardiac function, decreased myocardial infarct size, enzyme activity, oxidative stress, and apoptosis. In addition, ICA treatment lead to an increased p-Akt level, which was partially reversed by LY294002, a PI3 K pathway inhibitor. Conclusion Our study suggests that ICA has a cardioprotective effect against I/R injury, which is associated with its antioxidative and anti-apoptotic effect, at least partially, through the activation of PI3 K-Akt signaling pathway. [ABSTRACT FROM AUTHOR]