title: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. mhoriba@riem.nagoya-u.ac.jp
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Horiba
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.forename: Kenji
authors.initials: K
authors.lastname: Yasui
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Takenaka
authors.forename: Arihiro
authors.initials: A
authors.lastname: Sumida
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.forename: Sadatoshi
authors.initials: S
authors.lastname: Sakuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000078792:Midkine; D020011:Protective Agents / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D016207:Cytokines; D020011:Protective Agents; D000078792:Midkine