Aspirin ameliorates pulmonary vascular remodeling in pulmonary hypertension by dampening endothelial-to-mesenchymal transition
Aspirin ameliorates pulmonary vascular remodeling in pulmonary hypertension by dampening endothelial-to-mesenchymal transition
复制标题
阿司匹林通过抑制内皮间质转化改善肺动脉高压的肺血管重塑
DOI：
10.1016/j.ejphar.2021.174307
复制
发表时间：
2021-07-12
影响因子：
5
通讯作者：
Hu, Chang-Ping
中科院分区：
文献类型：
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作者：
Huang, Ning;Zhu, Tian-Tian;Hu, Chang-Ping
肺血管重构（PVR）是肺动脉高压（PH）的病理基础。对PVR病因的不完全理解阻碍了这种毁灭性疾病的药物开发，尽管目前可用的治疗方法，但其预后不良。内皮细胞向间质细胞转化（EndMT）是一种细胞转分化过程，近年来已被证实与包括PH在内的心血管疾病有关，但EndMT的发生机制以及如何在体内靶向EndMT等问题仍有待进一步研究。在此，通过进行苏木精-伊红和免疫荧光染色、透射电子显微镜和蛋白质印迹，我们发现EndMT在PH的发病机制中起关键作用，并且重要的是，FDA批准的广泛使用的药物阿司匹林能够改善缺氧诱导的PH的临床前大鼠模型中的PVR。此外，阿司匹林通过抑制HIF-1 α/TGF-β 1/Smads/Snail信号通路对EndMT的抑制作用。我们的数据表明，EndMT代表了一个有趣的药物靶点，用于预防和治疗缺氧性PH，阿司匹林可能会被重新利用，以满足缺氧性PH患者的紧急治疗需求。
Pulmonary vascular remodeling (PVR) is the pathological basis of pulmonary hypertension (PH). Incomplete understanding of PVR etiology has hindered drug development for this devastating disease, which exhibits poor prognosis despite the currently available therapies. Endothelial-to-mesenchymal transition (EndMT), a process of cell transdifferentiation, has been recently implicated in cardiovascular diseases, including PH. But the questions of how EndMT occurs and how to pharmacologically target EndMT in vivo have yet to be further answered. Herein, by performing hematoxylin-eosin and immunofluorescence staining, transmission electron microscopy and Western blotting, we found that EndMT plays a key role in the pathogenesis of PH, and importantly that aspirin, a FDA-approved widely used drug, was capable of ameliorating PVR in a preclinical rat model of hypoxia-induced PH. Moreover, aspirin exerted its inhibitory effects on EndMT in vitro and in vivo by suppressing HIF-1 alpha/TGF-beta 1/Smads/Snail signaling pathway. Our data suggest that EndMT represents an intriguing drug target for the prevention and treatment of hypoxic PH and that aspirin may be repurposed to meet the urgent therapeutic needs of hypoxic PH patients.