Gap Junction Intercellular Communication and Coronary Microvascular Disease in Type 2 Diabetes

Recent reports demonstrate that diabetic patients with coronary microvascular disease (CMD, also known as non‐obstructive coronary artery disease) exhibit higher cardiac mortality than diabetic patients without CMD. However, the molecular mechanisms in which diabetes leads to CMD are not well understood. In this study, we examine the role of gap junction intercellular communication in the development of CMD in diabetes. We used type 2 diabetic (T2D) mice induced by a single injection of low‐dose streptozotocin (75 mg/kg) with a high‐fat diet (60 % kcal). Coronary flow velocity reserve (CFVR) was measured in mice to assess coronary microvascular function and T2D mice showed significant decrease in CFVR compared to control mice, suggesting that T2D mice are suffering from CMD. Mouse coronary endothelial cells (MCECs) isolated from T2D mice and human coronary endothelial cells (HCECs) treated with high‐glucose exhibited the reduction of gap junction activity compared to their controls. Gap junction is composed of connexins (Cxs) and coronary endothelial cells express Cx37, Cx40, Cx43, and Cx45. Among those Cxs, Cx40 mRNA level was significantly decreased in MCECs isolated from T2D mice. Furthermore, Cx40 protein levels were significantly decreased in MCECs from inducible T2D mice, MCECs from spontaneous T2D mice (Tallyho mice), and HCECs from T2D patients compared to those controls. Cx40 knockout mice exhibited lower CFVR which was accompanied by decreased capillary density in the left ventricle (LV), when compared to the wild‐type mice. The potential causes of decreased capillary density include attenuated endothelial migration/proliferation and increased endothelial apoptosis. In ex vivo, high‐glucose treatment impaired capillary network formation in HCECs and Cx40 overexpression restored the level of capillary network in high‐glucose treated HCECs. We also found that Cx40 overexpression in T2D mice increased capillary density in the LV and CFVR. These data suggest that the downregulation of Cx40 decreases capillary density in the heart and leads to CMD in diabetes. Therefore, Cx40 overexpression in ECs could be the potential therapy for CMD in diabetic patients. Support or Funding Information This work was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL142214 and HL146764 to A. Makino).