Metformin Prevents High Glucose Induced Disruption of Coronary Artery Endothelial Barrier Function and Accelerates Wound Healing Via Regulating Junctional Protein, VE‐Cadherin

Abstract

Despite the great strides have been made in treating diabetes induced vascular endothelial barrier dysfunction, current treatments have shown limited success in reversing vascular pathologies. Increase in endothelial permeability via modification of endothelial junctional proteins, such as vascular endothelial cadherin (VE‐Cadherin), leads to the formation of minute inter‐endothelial gaps, and the infiltration of protein‐rich fluid in the interstitial space. If remained unchecked, the persistent buildup of edema underlying the endothelial lining sets the stage for the serious life‐threatening complications. Hyperglycemia‐induced endothelial dysfunction contributes vascular complications of diabetes. Moreover, wound healing impairment is also increasingly recognized to be a consequence of hyperglycemia‐induced dysfunction of endothelial in type 2 diabetes mellitus (T2DM). Metformin, an oral anti‐hyperglycemic agent, is the first‐line drug in the clinic for patients with T2DM. Clinical studies suggested that the beneficial effect of metformin on the incidence of diabetes complications was not only related to its action on blood glucose normalization. We hypothesized that the metformin prevents high glucose‐induced endothelial barrier dysfunction and accelerates wound healing process in human coronary endothelial cells (HCAE) via preventing the destabilization of VE‐cadherin. Endothelial permeability was evaluated by using Electric Cell‐substrate Impedance Sensing (ECIS) mechanism, a measure of trans‐endothelial electrical resistance (TEER) across the endothelial monolayers using TEER electrodes. Wound healing assay was performed by employing electric signals to both wound and monitor the healing process in endothelial monolayer. Our data show that 25mM glucose concentration increased endothelial permeability and abrogated the wound healing process. Metformin at the dose of 10mM significantly prevented alteration of endothelial barrier function and enhances wound healing process in the presence of high glucose concentration. To investigate the signaling mechanism involved in the protection offered by metformin, we found that metformin prevented myosin light chain kinase (MYLK) phosphorylation and increased in VE‐cadherin expression, suggesting abrogation of increase endothelial contractility and dismantling the junctional proteins in presence of high glucose concentration. In conclusion, our study shows that metformin maintained endothelial barrier function and improved the process of wound healing in endothelial cells exposed to high glucose. Thus, metformin is emerging as a potential therapeutics in improving coronary endothelial barrier function in diabetes mellitus.Support or Funding InformationThis work was supported by funding from CTRE SEED Grant Award to Mohammad Tauseef.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.