ErbB2 Expression on Left Ventricular Epicardial Endothelial Cells and CD105+ Cells is Decreased in Patients with Diabetes Mellitus.

Abstract Background 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). Methods 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 recepotrs was examined using multiparametric flow cytometry. Human microvascular endothelial cells (HMEC-1) and LV epicardial CD105+ non-endothelial cells were used to determine the effect of high glucose on ADAM10-dependent cleavage of ErbB receptors. Results We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2 on both endothelial cells and CD105+ non-endothelial cells. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high glucose in HMEC-1 and LV epicardial 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 expression of ErbB2. We also found high expression of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) on both endothelial cells and CD105+ non-endothelial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. Conclusions 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.