Arihiro Sumida

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.

Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction

AIM We have previously reported that therapy with midkine (MK) has a protective effect in mouse models of myocardial infarction (MI) and ischemia/reperfusion. The underlying mechanism was proved to be anti-apoptosis and prevention of left ventricular (LV) remodelling following angiogenesis. Here we investigated the effects of overexpression of MK by adenoviral gene transfer on cardiac function and remodelling in an experimental rat MI model. METHODS AND RESULTS MI was created in male Wistar rats. Adenoviral vectors encoding mouse MK (AdMK) or beta-galactosidase (AdLacZ; as controls) were injected in myocardium at the onset of MI. One week after injection, in vivo adenoviral gene expression was assessed by western blot and histological analysis. After echocardiographic analysis at 4 weeks and haemodynamic analysis at 6 weeks after MI, AdMK animals had better cardiac function compared with AdLacZ animals. Heart weight (HW) and relative HW of AdMK animals were not different from sham-operated animals after 6 weeks, pointing to a very potent effect in the prevention of ischemic cardiomyopathy. In histological studies at 6 weeks after MI, AdMK animals had less fibrosis in the non-infarcted myocardium and higher vascular density in the border-zone area compared with AdLacZ animals. AdMK animals had strongly upregulated levels of phosphorylated extracellular signal-regulated kinase, Akt, PI 3-kinase, and Bcl-2, whereas the level of Bax was downregulated compared with AdLacZ animals. CONCLUSION Overexpression of MK prevents LV remodelling and ameliorates LV dysfunction by anti-apoptotic and pro-angiogenic effects. MK gene transfer may provide a new therapeutic modality in ischemic cardiomyopathy and ischemic heart failure.

Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction

Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.

A single intracoronary injection of midkine reduces ischemia/reperfusion injury in Swine hearts: a novel therapeutic approach for acute coronary syndrome

Several growth factors are effective for salvaging myocardium and limiting infarct size in experimental studies with small animals. Their benefit in large animals and feasibility in clinical practice remains to be elucidated. We investigated the cardioprotective effect of midkine (MK) in swine subjected to ischemia/reperfusion (I/R). I/R was created by left anterior descending coronary artery occlusion for 45 min using a percutaneous over-the-wire balloon catheter. MK protein was injected as a bolus through the catheter at the initiation of reperfusion [MK-treated (MKT) group]. Saline was injected in controls (CONT). Infarct size/area at risk (24 h after I/R) in MKT was almost five times smaller than in CONT. Echocardiography in MKT revealed a significantly higher percent wall thickening of the interventricular septum, a higher left ventricular (LV) fractional shortening, and a lower E/e′ (ratio of transmitral to annular flow) compared with CONT. LV catheterization in MKT showed a lower LV end-diastolic pressure, and a higher dP/dtmax compared with CONT. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling-positive myocytes and CD45-positive cell infiltration in the peri-infarct area were significantly less in MKT than in CONT. Here, we demonstrate that a single intracoronary injection of MK protein in swine hearts at the onset of reperfusion dramatically reduces infarct size and ameliorates systolic/diastolic LV function. This beneficial effect is associated with a reduction of apoptotic and inflammatory reactions. MK application during percutaneous coronary intervention may become a promising adjunctive therapy in acute coronary syndromes.