title: An endogenously produced fragment of cardiac myosin-binding protein C is pathogenic and can lead to heart failure.
abstract: BACKGROUND
  A stable 40-kDa fragment is produced from cardiac myosin-binding protein C when the heart is stressed using a stimulus, such as ischemia-reperfusion injury. Elevated levels of the fragment can be detected in the diseased mouse and human heart, but its ability to interfere with normal cardiac function in the intact animal is unexplored.
  
  
  OBJECTIVE
  To understand the potential pathogenicity of the 40-kDa fragment in vivo and to investigate the molecular pathways that could be targeted for potential therapeutic intervention.
  
  
  RESULTS
  We generated cardiac myocyte-specific transgenic mice using a Tet-Off inducible system to permit controlled expression of the 40-kDa fragment in cardiomyocytes. When expression of the 40-kDa protein is induced by crossing the responder animals with tetracycline transactivator mice under conditions in which substantial quantities approximating those observed in diseased hearts are reached, the double-transgenic mice subsequently experience development of sarcomere dysgenesis and altered cardiac geometry, and the heart fails between 12 and 17 weeks of age. The induced double-transgenic mice had development of cardiac hypertrophy with myofibrillar disarray and fibrosis, in addition to activation of pathogenic MEK-ERK pathways. Inhibition of MEK-ERK signaling was achieved by injection of the mitogen-activated protein kinase (MAPK)/ERK inhibitor U0126. The drug effectively improved cardiac function, normalized heart size, and increased probability of survival.
  
  
  CONCLUSIONS
  These results suggest that the 40-kDa cardiac myosin-binding protein C fragment, which is produced at elevated levels during human cardiac disease, is a pathogenic fragment that is sufficient to cause hypertrophic cardiomyopathy and heart failure.
authors.affiliation: Department of Pediatrics, The Heart Institute, The Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Md Abdur
authors.initials: MA
authors.lastname: Razzaque
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: James
authors.initials: J
authors.lastname: Gulick
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012518:Sarcomeres / Q000737:chemistry; D000099163:Myosin Binding Protein C
chemical_list: D002070:Butadienes; D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D009570:Nitriles; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D000099163:Myosin Binding Protein C; C113580:U 0126
keywords: cardiomyopathies; contractile proteins; sarcomeres