Therapeutic Effect of Midkine on Cardiac Remodeling in Infarcted Rat Hearts

Fukui, Shinya; Kitagawa-Sakakida, Satoru; Kawamata, Sin; Matsumiya, Goro; Kawaguchi, Naomasa; Matsuura, Nariaki; Sawa, Yoshiki

doi:10.1016/j.athoracsur.2007.06.002

Cited by 31 publications

(33 citation statements)

References 27 publications

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“…Fukui et al (8) recently showed that MK has therapeutic effects for cardiac remodeling after MI. Although they did not show the detailed molecular mechanisms, the results were similar with our data in the point that the angiogenic effect of MK showed preventive action for LV remodeling.…”

Section: Discussionmentioning

confidence: 98%

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

Takenaka

Horiba²,

Ishiguro³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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Section: Discussionmentioning

confidence: 98%

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

Takenaka

Horiba²,

Ishiguro³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…17) MK also improves heart function upon chronic heart failure after ischemic injury. 143) , 144) Thus, in these diseases, MK itself is expected to be a potent therapeutic by promoting survival of damaged tissues (Table 3). MK produced by the yeast system is best suited for this purpose, since large scale production is possible and the yield of properly folded protein is high compared to production in bacteria.…”

Section: Inflammation and Repairmentioning

confidence: 99%

Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases

Muramatsu

2010

Proc. Jpn. Acad., Ser. B

174

173

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Midkine is a heparin-binding cytokine or a growth factor with a molecular weight of 13 kDa. Midkine binds to oversulfated structures in heparan sulfate and chondroitin sulfate. The midkine receptor is a molecular complex containing proteoglycans. Midkine promotes migration, survival and other activities of target cells. Midkine has about 50% sequence identity with pleiotrophin. Mice deficient in both factors exhibit severe abnormalities including female infertility. In adults, midkine is expressed in damaged tissues and involved in the reparative process. It is also involved in inflammatory reactions by promoting the migration of leukocytes, induction of chemokines and suppression of regulatory T cells. Midkine is expressed in a variety of malignant tumors and promotes their growth and invasion. Midkine appears to be helpful for the treatment of injuries in the heart, brain, spinal cord and retina. Midkine inhibitors are expected to be effective in the treatment of malignancies, rheumatoid arthritis, multiple sclerosis, renal diseases, restenosis, hypertension and adhesion after surgery.

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“…Apart from angiogenesis, additional research found that MK promoted the growth of mouse embryonic stem cells by inhibiting apoptosis through the PI3K/Akt signaling pathway [18]. Therefore, MK application is recently regarded as a new therapeutic strategy for the treatment of ischemic heart failure [19,20]. …”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

Zhao

Zhang

et al. 2014

Stem Cell Res Ther

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IntroductionElevated midkine (MK) expression may contribute to ventricular remodeling and ameliorate cardiac dysfunction after myocardial infarction (MI). Ex vivo modification of signaling mechanisms in mesenchymal stem cells (MSCs) with MK overexpression may improve the efficacy of cell-based therapy. This study sought to assess the safety and efficacy of MSCs with MK overexpression transplantation in a rat model of MI.MethodsA pLenO-DCE vector lentivirus encoding MK was constructed and infected in MSCs. MSC migration activity and cytoprotection was examined in hypoxia-induced H9C2 cells using transwell insert in vitro. Rats were randomized into five groups: sham, MI plus injection of phosphate buffered saline (PBS), MSCs, MSCs-green fluorescent protein (MSCs-GFP) and MSCs-MK, respectively. Survival rates were compared among groups using log-rank test and left ventricular function was measured by echocardiography at baseline, 4, 8 and 12 weeks.ResultsOverexpression of MK partially prevented hypoxia-induced MSC apoptosis and exerted MSC cytoprotection to anoxia induced H9C2 cells. The underlying mechanisms may be associated with the increased mRNA and protein levels of vascular endothelial growth factor (VEGF), transformation growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and stromal cell-derived factor 1 (SDF-1a) in MSCs-MK compared with isolated MSCs and MSCs-GFP. Consistent with the qPCR results, the culture supernatant of MSCs-MK had more SDF-1a (9.23 ng/ml), VEGF (8.34 ng/ml) and TGF-β1 (17.88 ng/ml) expression. In vivo, a greater proportion of cell survival was observed in the MSCs-MK group than in the MSCs-GFP group. Moreover, MSCs-MK administration was related to a significant improvement of cardiac function compared with other control groups at 12 weeks.ConclusionsTherapies employing MSCs with MK overexpression may represent an effective treatment for improving cardiac dysfunction and survival rate after MI.

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Therapeutic Effect of Midkine on Cardiac Remodeling in Infarcted Rat Hearts

Cited by 31 publications

References 27 publications

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

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

Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

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