Midkine Plays a Protective Role Against Cardiac Ischemia/Reperfusion Injury Through a Reduction of Apoptotic Reaction

Background— Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion. Methods and Results— Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type (Mdk+/+) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient (Mdk−/−) mice was larger than in Mdk+/+ mice (55.4±9.1% versus 32.1±5.3%, P<0.05). Terminal dUTP nick end-labeling–positive myocyte population in the periinfarct area in Mdk−/− mice was higher than in Mdk+/+ mice (6.8±0.9% versus 3.2±0.6%, P<0.05). Left ventricular fractional shortening 24 hours after I/R in Mdk−/− mice was significantly less than that in Mdk+/+ mice (34.3±4.4% versus 50.8±2.1%, P<0.05). Supplemental application of MK protein to left ventricle of Mdk−/− mice at the time of I/R resulted in reduction of the infarct size. Application of exogenous MK to cultured cardiomyocytes resulted in increased Bcl-2 expression and decreased apoptosis after hypoxia/reoxygenation. Conclusions— These results suggest that MK plays a protective role against I/R injury, most likely through a prevention of apoptotic reaction. MK is a potentially important new molecular target for treatment of ischemic heart disease.