c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia
Authors: Steven R Houser
Mikhail A Kolpakov
Daohai Yu
Abdelkarim Sabri
Rachid Seqqat
Bhopal Mohapatra
Khadija Rafiq
Hamid Band
Jianfen Guo
Wei An
Zhao Qi
Archana Sanjay
Neha Zutshi
Xinji Guo
Journal: Circulation (2014)
Discipline: CLINICAL MEDICINE
Keywords: angiogenesis; apoptosis; myocardial ischemia; ubiquitin.
Affiliations: 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)., 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). .

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. Methods and 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. 

Retracted: No

PubPeer comments:
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