c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia.
Circulation
; 129(20): 2031-43, 2014 May 20.
Article
in En
| MEDLINE
| ID: mdl-24583314
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 ANDRESULTS:
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.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Cardiomyopathy, Dilated
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Myocardial Ischemia
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Proto-Oncogene Proteins c-cbl
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Heart Failure
Limits:
Adult
/
Aged
/
Animals
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Year:
2014
Type:
Article