Homocysteine-induced endothelial dysfunction through mediating endoplasmic reticulum stress.

ObjectiveEndothelial dysfunction is a key pathological process in cardiovascular and cerebrovascular diseases. Herein, we aimed to investigate the effect of homocysteine on endoplasmic reticulum stress in a model of endothelial dysfunction, focusing on glucose-regulated protein 78 mediation by homocysteine.MethodsWe established a hyperhomocysteinemia model in mice to examine the effect of homocysteine on cerebral microcirculation. In vitro, endothelial cells were used to explore the effect of homocysteine on endoplasmic reticulum stress. We conducted a bioinformatics study to investigate the impact of homocysteine on the vascular microenvironment. Furthermore, molecular dynamics simulation analysis was performed to explore the binding mode and stability between homocysteine and glucose-regulated protein 78.ResultsIn vivo, homocysteine increased the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 in brain tissue, whereas reducing the expression of tight junction protein 1. Furthermore, inhibition of endoplasmic reticulum stress effectively improved endothelial dysfunction induced by homocysteine. Finally, molecular dynamics simulations revealed a critical interaction between homocysteine and glucose-regulated protein 78, which likely impacts binding affinity.ConclusionsHomocysteine causes cerebral microcirculatory disorders. The mechanism is related to homocysteine-induced endoplasmic reticulum stress through regulation of glucose-regulated protein 78 protein function.