The role and mechanism of JAK2 inhibitor in endothelial mesenchymal transition in systemic sclerosis

IF 4.6
Qingyan Luo , Xiaoheng Wang , Yanling Zhang , Wenrong Xie , Lina Liang , Yingping Xu , Yunshen Liang , Suyun Ji
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引用次数: 0

Abstract

Background

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and damage, immune dysregulation and fibrosis. Endothelial mesenchymal transition (EndoMT) has been implicated in the skin fibrosis of SSc. Many studies have demonstrated that janus kinase type2 (JAK2) inhibitor can alleviate skin fibrosis in both SSc patients and bleomycin (BLM)-induced mouse models of SSc. However, the potential therapeutic effect of JAK2 inhibitor on EndoMT in SSc skin, along with the underlying molecular mechanisms, remains unexplored.

Objective

To investigate the effects of JAK2 inhibitor on the EndoMT in SSc skin and to elucidate the associated molecular mechanisms.

Methods

Wild-type female C57BL/6 mice were divided into several groups to assess the effects of JAK2 inhibitor on EndoMT through H&E staining, masson staining, immunofluorescence and single-cell RNA-sequencing (scRNA-seq). Cultured human umbilical vein endothelial cells (HUVECs) were used to explore the mechanism of action of JAK2 inhibitor on EndoMT using immunofluorescence, quantitative RT-PCR, RNA sequencing and western blot.

Results

JAK2 inhibition improved skin fibrosis, reduced CD31/α-SMA co-localisation and the number of EndoMT-activated vascular endothelial cells in bleomycin-induced SSc mice. Treatment of HUVECs with TGF-β or BLM led to a myofibroblast-like morphology and markers, along with downregulation of endothelial cell features, which were reversed following JAK2 inhibition. The activation of the PI3K/Akt/mTOR pathway was involved in EndoMT in HUVECs induced by TGF-β/BLM, and this activation was attenuated by JAK2 inhibition.

Conclusions

JAK2 inhibitor may serve as an effective treatment for EndoMT in SSc, potentially through modulation of the PI3K/Akt/mTOR signaling pathway.
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CiteScore
7.60
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