Abstract 1263: Midkine Prevents Ventricular Remodeling After Myocardial Infarction Through Enhancement Of Angiogenesis Via PI3k/akt Pathway
Background: Midkine (MK) protein is a heparin-binding growth factor. We reported recently endogenous MK ameliorates not only acute myocardial infarction (MI) but also long-term survival after MI using MK knockout mice (MKKO). We aim to assess the therapeutic potential of MK protein after MI by exogenous application.
Method and results: MI was created in C57BL/6 mice (n=29) by ligation of the left coronary artery. In 11/29 mice, human recombinant MK protein was administrated for 28 days by osmotic pump intraperitoneally (MK-T). Saline was administrated in the same manner for control group (Control) (n=18). Survival rate 28 days after MI in MK-T was significantly higher than Control (82% vs. 44%, p<0.05). In echocardiography 28 days after MI, MK-T showed significantly better LV function compared to Control ( LVEDd; 4.3±0.5 vs. 6.0±0.4 mm, LVESd; 3.6±1.0 vs. 5.3±0.4 mm, EF; 44.3±10.1, vs. 32.1±0.6%, FS; 21.2±5.4 vs.15.3±0.3%, P<0.05). The serum BNP levels 28 days after MI in MK-T was significantly lower than that of Control (129 ± 5 pg/dl vs. 370 ± 98 pg/dl, P<0.05). Size of scar volume quantified by fibrosis area (picrosirius red) in MK-T was significantly smaller than Control (30.3 ± 5 vs. 52.3± 5%, p<0.05). The number of CD31-immunopositive cells in peri-infarct area of LV at 28 days in MK-T was significantly higher than those of Control (45.2 ± 5 V.S. 27.3 ± 5, p<0.05). These changes were associated with an activation of Akt phosphorylation (1.61 fold higher than control, p<0.05) in LV tissue. In-vitro experiments using human umbilical vein endothelial cells (HUVEC) with 100 ng/ml MK caused a significant increase of tube formation with enhacement of Akt phosphorylation (1.68 fold higher than control, P<0.05), and this upregulation was reversed completely by wortmannin, a specific inhibitor of PI3K.
Conclusion: MK protein prevents the cardiac remodeling after MI and improves the survival through enhancement of angiogenesis via PI3K/Akt pathway. Exogenous application of MK protein might be a new therapeutic strategy for treatment of heart failure.