title: Neuron-derived neurotrophic factor ameliorates adverse cardiac remodeling after experimental myocardial infarction.
abstract: BACKGROUND
  Myocardial infarction (MI) is one of the major causes of death worldwide. Chronic heart failure is a serious complication of MI that leads to poor prognosis. We recently found that neuron-derived neurotrophic factor (NDNF) is a proangiogenic secretory protein that is upregulated in ischemic skeletal muscle. Here, we examined whether NDNF modulates cardiac remodeling in response to chronic ischemia.
  
  
  RESULTS
  C57BL/6J wild-type mice were subjected to the permanent ligation of the left anterior descending coronary artery to create MI. Adenoviral vectors expressing NDNF or β-galactosidase (control) were intramuscularly injected into mice 3 days before permanent left anterior descending coronary artery ligation. Intramuscular administration of adenoviral vectors expressing NDNF to mice resulted in increased levels of circulating NDNF. Adenoviral vectors expressing NDNF administration improved left ventricular systolic dysfunction and dilatation after MI surgery. Moreover, adenoviral vectors expressing NDNF enhanced capillary formation and reduced cardiomyocyte apoptosis and hypertrophy in the post-MI hearts. Treatment of cultured cardiomyocytes with recombinant NDNF protein led to reduced apoptosis under conditions of hypoxia. NDNF also promoted the phosphorylation of Akt and focal adhesion kinase in cardiomyocytes. Blockade of focal adhesion kinase activation blocked the stimulatory effects of NDNF on cardiomyocyte survival and Akt phosphorylation. Similarly, treatment of cultured endothelial cells with NDNF protein led to enhancement of network formation and Akt phosphorylation, which was diminished by focal adhesion kinase inhibition.
  
  
  CONCLUSIONS
  These data suggest that NDNF ameliorates adverse myocardial remodeling after MI by its abilities to enhance myocyte survival and angiogenesis in the heart through focal adhesion kinase/Akt-dependent mechanisms.
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Yusuke
authors: Y
authors: Joki
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.). nouchi@med.nagoya-u.ac.jp ohashik@med.nagoya-u.ac.jp.
authors: Koji
authors: K
authors: Ohashi
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Daisuke
authors: D
authors: Yuasa
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Rei
authors: R
authors: Shibata
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Yoshiyuki
authors: Y
authors: Kataoka
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Takahiro
authors: T
authors: Kambara
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Yusuke
authors: Y
authors: Uemura
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Kazuhiro
authors: K
authors: Matsuo
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Satoko
authors: S
authors: Hayakawa
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Mizuho
authors: M
authors: Hiramatsu-Ito
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Noriyoshi
authors: N
authors: Kanemura
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Masanori
authors: M
authors: Ito
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Hayato
authors: H
authors: Ogawa
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Hiroyuki
authors: H
authors: Daida
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.).
authors: Toyoaki
authors: T
authors: Murohara
authors: From the Departments of Cardiology (Y.J., D.Y., R.S., Y.K., T.K., Y.U., K.M., S.H., M.H.-I., N.K., M.I., H.O., T.M.) and Molecular Cardiovascular Medicine (K.O., N.O.), Nagoya University Graduate School of Medicine, Japan; and Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan (Y.J., H.D.). nouchi@med.nagoya-u.ac.jp ohashik@med.nagoya-u.ac.jp.
authors: Noriyuki
authors: N
authors: Ouchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D051417:Focal Adhesion Kinase 1 / Q000502:physiology; D007273:Injections, Intramuscular; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
chemical_list: C561304:NDNF protein, mouse; D009414:Nerve Growth Factors; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; NDNF protein, mouse; cardiovascular remodeling, ventricular; focal adhesion protein-tyrosine kinase; myocardial infarction