Role of Connexin40 in Coronary Endothelial Cell Dysfunction in Type 1 Diabetic Mice

Abstract

Gap junction intercellular communication (GJIC) in the endothelium plays an important role in regulating vascular tone and in revascularization, although little is known about the contribution of connexins (Cxs, component of GJIC) to vascular complications in the diabetic heart. Coronary endothelial cells (ECs) isolated from diabetic mice exhibit lower protein levels of Cx37 and Cx40 (but not Cx43) and less GJIC than control. Vasodilatation induced by endothelium‐dependent hyperpolarization was significantly reduced in diabetic coronary artery (CA). The Cx40‐specific inhibitory peptide, 40GAP27, attenuated endothelium‐dependent relaxation in diabetic CA at the concentration that does not affect the relaxation in control CA, suggesting that the total amount of Cx40 is lower in diabetic CA than in control CA. In diabetic mice, coronary capillary density was significantly decreased in vivo. In vitro, GJIC inhibitor attenuated EC capillary network formation. High glucose treatment caused a decrease in Cx40 protein expression in ECs and impaired EC capillary network formation. Furthermore, we found that the decrease in Cx40 might be due to the lowered protein expression of Sp1, a transcriptional factor that regulates Cx40 expression. These data indicate that downregulation of Cx40 protein expression and resultant inhibition of GJIC contribute to coronary vascular complication in diabetes.