title: FLT3 activation improves post-myocardial infarction remodeling involving a cytoprotective effect on cardiomyocytes.
abstract: OBJECTIVE
  The goal of this study was to define the role of FMS-like tyrosine kinase 3 (FLT3) in the heart.
  
  
  BACKGROUND
  FLT3 is a prominent target of receptor tyrosine kinase inhibitors (TKIs) used for anticancer therapy. TKIs can cause cardiomyopathy but understanding of the mechanisms is incomplete, partly because the roles of specific TKI target receptors in the heart are still obscure.
  
  
  METHODS
  Myocardial infarction was induced in mice by permanent ligation of the left anterior descending coronary artery followed by intramyocardial injection of FLT3 ligand (FL) or vehicle into the infarct border zone. Cardiac morphology and function were assessed by echocardiography and histological analysis 1 week after infarction. In addition, FLT3 expression and regulation, as well as molecular mechanisms of FLT3 action, were examined in cardiomyocytes in vitro.
  
  
  RESULTS
  The intramyocardial injection of FL into the infarct border zone decreased infarct size and ameliorated post-myocardial infarction remodeling and function in mice. This beneficial effect was associated with reduced apoptosis, including myocytes in the infarct border zone. Cardiomyocytes expressed functional FLT3, and FLT3 messenger ribonucleic acid and protein were up-regulated under oxidative stress, identifying cardiomyocytes as FL target cells. FLT3 activation with FL protected cardiomyocytes from oxidative stress-induced apoptosis via an Akt-dependent mechanism involving Bcl-2 family protein regulation and inhibition of the mitochondrial death pathway.
  
  
  CONCLUSIONS
  FLT3 is a cytoprotective system in the heart and a potential therapeutic target in ischemic cardiac injury. The protective mechanisms uncovered here may be further explored in view of potential cardiotoxic effects of FLT3-targeting anticancer therapy, particularly in patients with ischemic heart disease.
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Otmar
authors.initials: O
authors.lastname: Pfister
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Vera
authors.initials: V
authors.lastname: Lorenz
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Angelos
authors.initials: A
authors.lastname: Oikonomopoulos
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Stéphanie P
authors.initials: SP
authors.lastname: Häuselmann
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mbah
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Cardiology, University Hospital Basel, Basel, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Kaufmann
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wodnar-Filipowicz
authors.affiliation: Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Cardiology, University Hospital Basel, Basel, Switzerland. Electronic address: gabriela.kuster@usb.ch.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Kuster
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D015552:Injections, Intralesional; D008024:Ligands; D008565:Membrane Proteins / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein
keywords: apoptosis; heart failure; hematopoietic cytokines; myocardial infarction; receptor tyrosine kinase; remodeling