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

Abstract

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.

Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells

“…The phosphorylated cytoplasmic tail of LRP1 associates with Shc, a cellular docking protein, and LRP1 modulates JNK, a member of the MAP kinase family (Barnes et al, 2001;Lutz et al, 2002). Finally, both MK and LRP1 are induced by hypoxia, which is often manifested in carcinoma tissues (Horiba et al, 2006;Koong et al, 2000;Reynolds et al, 2004). These data collectively suggest overlapping functions of MK and LRP1 in cancer development, and are consistent with the findings presented in this paper.…”

Midkine Promotes Atherosclerotic Plaque Formation Through Its Pro-Inflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein E-Knockout Mice

“…These anti-apoptotic effects of MK are in agreement with recently reported findings in a congestive heart failure mouse model. 21, 47 Regarding clinical manifestations of atherogenesis, serum MK levels are significantly increased in obese human subjects, 17 and MK is present in the thickened intima of fatty streaks and advanced atherosclerotic regions in human atheromatous plaques. 18 Moreover, serum MK levels were significantly higher in patients with severe peripheral artery disease than in healthy controls.…”

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

“…According to others (45,46), injection of recombinant MDK is expected to induce a CD4 ϩ T cell response in humans beings with a limited amplitude and consequently be poorly immunogenic (42,43,47). This could be an advantage for therapeutic applications of the MDK protein to treat cardiac ischemia (48) and neuronal disorders (49).…”