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.
JAK2抑制剂在系统性硬化症内皮间质转化中的作用及机制。
背景:系统性硬化症(SSc)是一种以血管内皮功能障碍和损伤、免疫失调和纤维化为特征的自身免疫性疾病。内皮间充质转化(EndoMT)与SSc的皮肤纤维化有关。许多研究表明,janus kinase type2 (JAK2)抑制剂可以减轻SSc患者和bleomycin (BLM)诱导的SSc小鼠模型的皮肤纤维化。然而,JAK2抑制剂对SSc皮肤EndoMT的潜在治疗作用以及潜在的分子机制仍未被探索。目的:探讨JAK2抑制剂对SSc皮肤EndoMT的影响及其分子机制。方法:将野生型雌性C57BL/6小鼠分为几组,通过H&E染色、masson染色、免疫荧光和单细胞rna测序(scRNA-seq)评估JAK2抑制剂对EndoMT的影响。利用培养的人脐静脉内皮细胞(HUVECs),采用免疫荧光、定量RT-PCR、RNA测序和western blot等方法探讨JAK2抑制剂对内皮细胞EndoMT的作用机制。结果:JAK2抑制改善了博莱霉素诱导的SSc小鼠的皮肤纤维化,减少了CD31/α-SMA共定位和endomt激活的血管内皮细胞数量。用TGF-β或BLM处理HUVECs导致肌成纤维细胞样形态和标记,以及内皮细胞特征的下调,这些在JAK2抑制后逆转。在TGF-β/BLM诱导的HUVECs中,PI3K/Akt/mTOR通路的激活参与了EndoMT,并且这种激活被JAK2抑制而减弱。结论:JAK2抑制剂可能通过调节PI3K/Akt/mTOR信号通路,有效治疗SSc中的EndoMT。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
7.60
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