title: Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Huro-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Sumida
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Horiba
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Takenaka
authors.forename: Norihiro
authors.initials: N
authors.lastname: Ueda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ooboshi
authors.forename: Tobias
authors.initials: T
authors.lastname: Opthof
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006439:Hemodynamics / Q000502:physiology; D015552:Injections, Intralesional; D007763:Lac Operon; D008297:Male; D051379:Mice; D000078792:Midkine; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018487:Ventricular Dysfunction, Left / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D016207:Cytokines; D019253:Proto-Oncogene Proteins c-bcl-2; D000078792:Midkine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases