Abstract
Introduction and Hypothesis: Proteasome degradation of ubiquitin-targeted proteins plays an important role in the development of cardiomyopathy and heart failure. The mechanisms that control proteasome function and protein ubiquitination and turnover remain poorly defined. The proto-oncogene Casitas b-lineage lymphoma (Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets tyrosine kinases, resulting in their ubiquitination and down-regulation. Although Cbl is a crucial signaling molecule in many cells, the role of Cbl in the heart is unknown. Methods and Results: We show increased Cbl expression in human failing hearts and in response to pathological stress stimuli in mice. Cbl deficient mice demonstrated a more robust functional recovery after ischemia reperfusion injury, as well as significantly reduced myocyte apoptosis and epidermal growth factor receptor and focal adhesion (FA) protein ubiquitination and downregulation. Cbl Knockdown in-vitro protected cardiomyocytes against H2O2-induced apoptosis. Cbl deficient mice also show greater functional recovery after myocardial ischemia. This cardioprotective effect of Cbl deletion can be attributed, at least in part, to enhanced neoangiogenesis in the infarcted region via upregulation of vascular endothelial growth factor-a. Conclusions: Cbl activation regulates myocyte apoptosis and angiogenesis and contributes to adverse cardiac remodeling post-MI. These findings point to Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling post-MI.
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