title: Activated Met signalling in the developing mouse heart leads to cardiac disease.
abstract: BACKGROUND
  The Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine involved in many physiological processes, including skeletal muscle, placenta and liver development. Little is known about its role and that of Met tyrosine kinase receptor in cardiac development.
  
  
  RESULTS
  In this study, we generated two transgenic mice with cardiac-specific, tetracycline-suppressible expression of either Hepatocyte Growth Factor (HGF) or the constitutively activated Tpr-Met kinase to explore: i) the effect of stimulation of the endogenous Met receptor by autocrine production of HGF and ii) the consequence of sustained activation of Met signalling in the heart. We first showed that Met is present in the neonatal cardiomyocytes and is responsive to exogenous HGF. Exogenous HGF starting from prenatal stage enhanced cardiac proliferation and reduced sarcomeric proteins and Connexin43 (Cx43) in newborn mice. As adults, these transgenics developed systolic contractile dysfunction. Conversely, prenatal Tpr-Met expression was lethal after birth. Inducing Tpr-Met expression during postnatal life caused early-onset heart failure, characterized by decreased Cx43, upregulation of fetal genes and hypertrophy.
  
  
  CONCLUSIONS
  Taken together, our data show that excessive activation of the HGF/Met system in development may result in cardiac damage and suggest that Met signalling may be implicated in the pathogenesis of cardiac disease.
authors.affiliation: Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Leo
authors.forename: Valentina
authors.initials: V
authors.lastname: Sala
authors.forename: Mara
authors.initials: M
authors.lastname: Morello
authors.forename: Amedeo
authors.initials: A
authors.lastname: Chiribiri
authors.forename: Ilan
authors.initials: I
authors.lastname: Riess
authors.forename: Daniele
authors.initials: D
authors.lastname: Mancardi
authors.forename: Stefano
authors.initials: S
authors.lastname: Schiaffino
authors.forename: Carola
authors.initials: C
authors.lastname: Ponzetto
authors.forename: Tiziana
authors.initials: T
authors.lastname: Crepaldi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000254:growth & development* / Q000503:physiopathology; D006331:Heart Diseases / Q000201:enzymology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018031:Connexin 43; D009124:Muscle Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met