This Article Full Text Full Text (PDF) All Versions of this Article: 114/16/1713    most recent CIRCULATIONAHA.106.632273v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Horiba, M. Articles by Kodama, I. Search for Related Content PubMed PubMed Citation Articles by Horiba, M. Articles by Kodama, I. Related Collections Apoptosis Physiological and pathological control of gene expression

(Circulation. 2006;114:1713-1720.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

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

Mitsuru Horiba, MD; Kenji Kadomatsu, MD; Kenji Yasui, MD; Jong-Kook Lee, MD; Hiroharu Takenaka, MD; Arihiro Sumida, MD; Kaichiro Kamiya, MD; Sen Chen, MD; Sadatoshi Sakuma, PhD; Takashi Muramatsu, PhD; Itsuo Kodama, MD

From the Department of Cardiovascular Research (M.H., J.-K.L, H.T., A.S., K. Kamiya, I.K.) and Bio-information Analysis (K.Y.), Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Biochemistry, Nagoya University Graduate School of Medicine (K. Kadomatsu, S.C.), Nagoya, Japan; Cell Signals Inc (S.S.), Yokohama, Japan; and Department of Health Science, Faculty of Psychological and Physical Sciences (T.M.), Aichi Gakuin University, Nisshin, Japan.

Correspondence to Mitsuru Horiba, Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail mhoriba{at}riem.nagoya-u.ac.jp

Received April 6, 2006; revision received August 3, 2006; accepted August 7, 2006.

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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				S. Fukui, S. Kitagawa-Sakakida, S. Kawamata, G. Matsumiya, N. Kawaguchi, N. Matsuura, and Y. Sawa Therapeutic Effect of Midkine on Cardiac Remodeling in Infarcted Rat Hearts Ann. Thorac. Surg., February 1, 2008; 85(2): 562 - 570. [Abstract] [Full Text] [PDF]

				S. Chen, G. Bu, Y. Takei, K. Sakamoto, S. Ikematsu, T. Muramatsu, and K. Kadomatsu Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells J. Cell Sci., November 15, 2007; 120(22): 4009 - 4015. [Abstract] [Full Text] [PDF]