Extracellular Ubiquitin Modulates Cardiac Fibroblast Phenotype and Function

Stimulation of β-adrenergic receptor (β-AR) increases extracellular levels of ubiquitin (UB), and extracellular UB inhibits β-AR-stimulated apoptosis. In the heart, exogenous UB affects β-AR-stimulated increases in left ventricular function, and decreases myocardial apoptosis and fibrosis. Cardiac fibroblasts are vital for maintaining the normal function of the heart, and are integral in the structural remodeling of the heart in response to injury or stress. Here we used adult rat cardiac fibroblasts to test the hypothesis that UB modulates cardiac fibroblast phenotype and function, thereby decreasing myocardial fibrosis. Using FITC-labeled UB and confocal microscopy, we first provide evidence that extracellular UB is internalized into cellular compartments within 30-60 min. Immunocytochemical analysis using anti-Ki-67 antibodies showed that UB treatment inhibits the proliferation of actively growing fibroblasts within 24 h. UB treatment decreased the formation of lamellipodia and filopodia projections wh...