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

Abstract

IntroductionAtherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. 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 eHsp90α involved in diabetic atherosclerosis.Research design and methodsOne 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.ResultsThe level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90α 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 Hsp90α was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase eHsp90α secretion under stress. Then inhibition of eHsp90α can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90α increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression.ConclusionseHsp90α plays a critical role in the early inflammatory injury stage of atherosclerosis.Trial registration numberNCT04787770.

RETRACTED: Risk factors for amputation in diabetic foot ulcers: A retrospective analysis

“…7,8 In order to further understand the levels of more inflammatory markers and their influencing factors in DFU amputation patients, it is important for clinical guidance of patient treatment. 9 This study conducted a retrospective study on the data of hospitalized DFU patients admitted to our hospital from October 2019 to October 2023, aiming to understand and analyse the levels of laboratory inflammatory factors and their influencing factors in patients with amputation of DFUs, so as to provide a feasible reference for clinical treatment and disease prevention.…”

“…Inflammatory factors and markers, such as tumour necrosis factor‐α (TNF‐α), have been shown to be elevated in patients with DFUs and associated with poor wound healing and an increased risk of amputation, but there has been relatively little research on other inflammatory markers 7,8 . In order to further understand the levels of more inflammatory markers and their influencing factors in DFU amputation patients, it is important for clinical guidance of patient treatment 9 …”

Targeting extracellular Hsp90: A unique frontier against cancer

“…Surface expression of Hsp90 on endothelial cells can also be increased by oxidative stress ( Profumo et al, 2018 ). This has been suggested in the context of atherosclerotic plaques; eHsp90 has been seen to be the target of autoimmune responses in patients with carotid atherosclerosis, and increased eHsp90 was associated with diabetic vascular disease ( Businaro et al, 2009 ; Profumo et al, 2018 ; Ding et al, 2022 ). Through LRP1, eHsp90 enhanced monocyte migration in the inflammatory injury associated with atherosclerosis ( Ding et al, 2022 ).…”

“…This has been suggested in the context of atherosclerotic plaques; eHsp90 has been seen to be the target of autoimmune responses in patients with carotid atherosclerosis, and increased eHsp90 was associated with diabetic vascular disease ( Businaro et al, 2009 ; Profumo et al, 2018 ; Ding et al, 2022 ). Through LRP1, eHsp90 enhanced monocyte migration in the inflammatory injury associated with atherosclerosis ( Ding et al, 2022 ). Plasma levels of Hsp90 have also been shown to be elevated in patients with systemic sclerosis and associated with increased inflammatory activity and worse lung function ( Storkanova et al, 2021 ).…”

Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

“…eNOS is responsible for the production of most of the vascular NO, deficiency in which can promote atherogenesis [ 177 ]. Further support for a role of Hsp90α in atherosclerosis and diabetes came from the finding that the levels of eHsp90α were upregulated in patients with aggravated diabetic vascular disease [ 178 ]. eHsp90 recruits monocytes through LRP1 activation, which indicates a connection between Hsp90α and inflammatory damage in diabetic vascular complications.…”