Moscatilin 通过激活 IL13RA2 依赖性抑制 STAT3 和削弱 WNT3/β-catenin 信号通路来抑制血管钙化。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research Pub Date : 2025-02-01 DOI:10.1016/j.jare.2024.02.020

Tingting Zhang , Mengmeng Zhu , Jialing Ma , Zhenghong Liu , Zhidan Zhang , Meijie Chen , Yaping Zhao , Huaxin Li , Shengnan Wang , Xiaoning Wei , Wenwen Zhang , Xiaoxiao Yang , Peter J. Little , Danielle Kamato , Hao Hu , Yajun Duan , Baotong Zhang , Jianbo Xiao , Suowen Xu , Yuanli Chen

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引用次数: 0

摘要

导言：血管钙化是伴随动脉粥样硬化性心血管疾病和慢性肾脏病的一种破坏性血管并发症，会增加不良心血管事件的发生率，并损害血管干预的效果。然而，目前还缺乏有效的治疗药物和疗法来延缓或预防血管钙化：本研究旨在检测霍山石斛（一种著名中药）中的莫斯卡替林在体外、体内和体外抑制血管钙化的疗效和机制：方法：雄性C57BL/6J小鼠（25周龄）经尼古丁和维生素D3（VD3）处理后诱导血管钙化。在体外，我们建立了磷酸条件下人主动脉平滑肌细胞（HASMC）成骨的细胞模型：通过使用内部药物筛选方案，我们发现了一种新的天然化学实体 Moscatilin，它可以减少 HASMC 的钙积累。在培养的 HASMCs 中验证了 Moscatilin 对血管钙化的保护作用。无偏见的转录谱分析和细胞热转移分析表明，莫斯卡替林通过与白细胞介素13受体亚基A2（IL13RA2）结合并增强其表达来抑制血管钙化。此外，IL13RA2在HASMC成骨过程中减少，从而通过STAT3促进了炎症因子的分泌。我们进一步验证了莫斯卡替林抑制血管钙化的经典WNT/β-catenin通路的参与，其中WNT3在这一过程中起着关键作用。莫斯卡替林减轻了WNT3/β-catenin和IL13RA2/STAT3之间的串扰，从而减少了HASMCs的成骨分化：本研究支持莫斯卡替林作为一种新的天然候选药物，通过调节 IL13RA2/STAT3 和 WNT3/β -catenin 信号通路来治疗血管钙化。

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Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway

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Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway

Introduction

Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking.

Objectives

This study was designed to test the therapeutic effects and mechanism of Moscatilin (also known as dendrophenol) from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo.

Methods

Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D₃ (VD₃) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions.

Results

By utilizing an in-house drug screening strategy, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/β-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/β-catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs.

Conclusion

This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/β-catenin signalling pathways.

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来源期刊

Journal of Advanced Research Multidisciplinary-Multidisciplinary

CiteScore

21.60

自引率

0.90%

发文量

280

审稿时长

12 weeks

期刊介绍： Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.