Abstract
We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105+ cells obtained from cardiac biopsies of patients undergoing coronary artery bypass grafting surgery (CABG). Endothelial cells and CD105+ non-endothelial cells were freshly isolated from LV epicardial biopsies obtained from 15 subjects with diabetes mellitus (DM) and 8 controls. The expression of ErbB receptors was examined using flow cytometry. We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high Glucose in human microvascular endothelial cells (HMEC-1) and CD105+ non-endothelial cells, using a novel flow cytometric approach to simultaneously determine the total level, cell surface expression, and phosphorylation of ErbB2. Incubation of cells in the presence of 25 mM d-glucose resulted in decreased cell surface but not total levels of ErbB2. The level of ErbB2 at the cell surface is controlled by disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) that is expressed on LV epicardial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. We suggest that high Glucose depresses ErbB receptor signaling in endothelial cells and cardiac progenitor cells via the promotion of ADAM10-dependent cleavage of ErbB2 at the cell surface, thus contributing to vascular dysfunction and adverse remodeling seen in diabetic patients.