Endothelial protective effect of rapamycin against simulated ischemia injury through up-regulation of autophagy and inhibition of endoplasmic reticulum stress

Abstract

Introduction: Rapamycin has been shown to have cytoprotective properties in some experimental models of ischemia. However, the precise molecular mechanisms underlying the positive effect of rapamycin on endothelial cells in ischemic injury remain unknown. It is very important because endothelial cells are firstly exposed to ischemia and play an important role in ischemic organ damage. Autophagy and endoplasmic reticulum stress are suggested to be implicated in hypoxic/ischemic injury of endothelial cells. This study aims to explore whether the endothelial protective effect of rapamycin is associated with exacerbation of autophagy and attenuation of endoplasmic reticulum stress. Material and methods: The protective effects of rapamycin against oxygen and glucose deprivation (OGD)-induced cell injury were explored in human vascular endothelial cells (HUVECs). Cell viability was measured by MTT assay. The protein levels of Beclin 1, p62, p-mTOR, p-S6K, p-4EBP, GRP78, p-PERK and p-IRE1 were analyzed using immunoblotting. Results: Rapamycin in the simulated ischemia model increased the cell viability, indicating its cytoprotective effect (p < 0.05). Experiments with 3-methyladenine as an inhibitor of autophagy and thapsigargin as an inducer of endoplasmic reticulum stress support that rapamycin exerts endothelial protective effects against OGD-induced damage via autophagy-endoplasmic reticulum stress pathway. Conclusions: This study demonstrated that rapamycin protects ischemic HUVECs via down-regulation of the mTOR pathway, enhancement of autophagy and inhibition of endoplasmic reticulum stress.

Human tendon-on-a-chip for modeling vascular inflammatory fibrosis

“…This underscores a predominant influence of rapamycin on the inflamed vascular endothelium, likely associated with the enhanced vascular barrier integrity observed post-rapamycin treatment ( Fig. 5c ), which is consistent with published reports of rapamycin’s cytoprotective effects against endothelial cell damage 25 . The GO BP terms enriched by DEGs in the vascular and tissue hydrogel compartments were then examined.…”