c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia.
- Authors
- Seqqat, Rachid
- Format
- Article
- Status
- publishedVersion
- Description
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.
Universidad De Las Fuerzas Armadas
http://www.ncbi.nlm.nih.gov/pubmed/24583314
https://www.scopus.com/record/display.uri?eid=2-s2.0-84901197890&origin=resultslist&sort=plf-f&src=s&st1=
- Publication Year
- 2014
- Language
- eng
- Topic
- INHIBITION
CARDIAC
FUNCTION
MYOCARDIAL
- Repository
- Repositorio SENESCYT
- Rights
- openAccess
- License
- openAccess