title: c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia.
abstract: BACKGROUND
  The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia.
  
  
  RESULTS
  We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl-deficient mice demonstrated a more robust functional recovery after myocardial ischemia/reperfusion injury and significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor type 2 in the infarcted region.
  
  
  CONCLUSIONS
  c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis, and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia.
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Khadija
authors.initials: K
authors.lastname: Rafiq
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kolpakov
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Rachid
authors.initials: R
authors.lastname: Seqqat
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Jianfen
authors.initials: J
authors.lastname: Guo
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Xinji
authors.initials: X
authors.lastname: Guo
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Zhao
authors.initials: Z
authors.lastname: Qi
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Bhopal
authors.initials: B
authors.lastname: Mohapatra
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Neha
authors.initials: N
authors.lastname: Zutshi
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Wei
authors.initials: W
authors.lastname: An
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Archana
authors.initials: A
authors.lastname: Sanjay
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay).
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: From the Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (K.R., M.A.K., R.S., J.G., X.G., Z.Q., D.Y., S.R.H., A. Sabri); Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha (B.M., N.Z., W.A., H.B.); and Department of Surgery, University of Connecticut Health Center, Farmington (A. Sanjay). sabri@temple.edu.
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Sabri
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006328:Cardiac Catheterization; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C067419:CBL protein, human; C493849:Cbl protein, mouse
keywords: angiogenesis; apoptosis; myocardial ischemia; ubiquitin