Extracellular Hsp90α, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes

Introduction Atherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosderosis. Extracellular heat shock protein 90 (eHsp90) is secreted into the serum and is involved in various physiological and pathophysiological processes. However, the specific mechanism of eHsp90 in early atherosclerosis remains unclear. This study explored the relationship between Hsp90 and diabetic lower extremity arterial disease and investigated the expression of eHsp90 in vascular endothelial cells under environmental stimulation and the function and mechanism of Hsp90 alpha involved in diabetic atherosderosis. Research design and methods One hundred and three selected patients were divided into three groups: the diabetes mellitus group (n=27), the diabetic lower extremity arterial disease group (n=46), and the diabetic critical limb ischemia group (n=30). The relationships among serum Hsp90, oxidative stress indexes, and patient outcomes and the correlations among the indexes were analyzed. H&E staining and immunohistochemistry were used to observe the vasculature of amputated feet from patients with diabetic foot. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression. Results The level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90 alpha was correlated with malondialdehyde to some extent and was an independent risk factor in the progression of diabetic vascular disease, with predictive ability. The expression area of Hsp90 alpha was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase Hsp90 alpha secretion under stress. Then inhibition of Hsp90 alpha can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90 alpha increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression. Conclusions Hsp90 alpha plays a critical role in the early inflammatory injury stage of atherosclerosis.

Automated summary

This study investigated the role of Hsp90 in diabetic lower extremity arterial disease and its involvement in diabetic atherosclerosis. The results showed that serum Hsp90 levels were upregulated in patients with worsening diabetic vascular disease. Hsp90 alpha was found to be correlated with malondialdehyde and was identified as an independent risk factor for the progression of diabetic vascular disease. In addition, the expression of Hsp90 alpha was consistent with inflammatory infiltration in blood vessels. Under stress, vascular endothelial cells were observed to increase the secretion of Hsp90 alpha, and inhibition of Hsp90 alpha reduced inflammation and damage. Furthermore, endothelial cell-conditioned medium and recombinant human Hsp90 alpha were found to promote monocyte migration through the low-density lipoprotein receptor-related protein 1 (LRP1) receptor, thereby contributing to disease progression. These findings suggest that Hsp90 alpha plays a critical role in the early inflammatory injury stage of atherosclerosis.