Targeting eHsp90α/GRP78 signaling-mediated endothelial barrier dysfunction in diabetic atherosclerosis: evidence from clinical and experimental studies.

BACKGROUND

Early detection of diabetic atherosclerosis (DAS) remains challenging, and the mechanisms underlying endothelial barrier dysfunction in this condition are not fully understood. Extracellular Hsp90α (eHsp90α) and the ER stress marker GRP78 have been implicated in vascular injury; however, their roles in DAS remain unclear. Therefore, this study aimed to investigate the association of eHsp90α and GRP78 with DAS and explore the underlying mechanisms.

METHODS

We recruited patients with diabetes mellitus (DM) and patients with DAS. We then compared the levels and potential efficacies of serum eHsp90α and the ER stress marker GRP78 between the two groups. We subsequently conducted cytological experiments and experiments with ApoE-/- mice to further explore the underlying mechanisms involved.

RESULTS

The serological analysis revealed that the levels of serum eHsp90α and the ER stress marker GRP78 were significantly higher in the DAS group than in the DM group and that the eHsp90α level was correlated with GRP78 level. The association and preliminary discriminative performance of the combination of eHsp90α and GRP78 levels were appeared higher than that of either marker alone. In addition, GRP78 plays a mediating role in the relationship between eHsp90α and DAS. Furthermore, the expression of GRP78 was higher in both diabetic ApoE-/- mice and DAS patients than in control ApoE-/- mice and AS patients. Cytological experiments revealed that eHsp90α induced endothelial barrier dysfunction mediated by ER stress via the LRP1 receptor.

CONCLUSIONS

Our findings suggest that eHsp90α and GRP78 are associated with diabetic atherosclerosis and may be associated biomarkers with potential discriminative value, although further validation is required. The eHsp90α-LRP1-ER stress pathway may contribute to endothelial barrier dysfunction. However, further large-scale and longitudinal studies are required to validate these findings.