Affiliation:
1. Haihe Laboratory of Modern Chinese Medicine Tianjin University of Traditional Chinese Medicine Tianjin China
2. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research Nankai University Tianjin China
3. The Affiliated Hospital of Henan University of Chinese Medicine Zhengzhou China
4. Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co‐constructed by Henan Province and Education Ministry of China Henan University of Chinese Medicine Zhengzhou China
Abstract
AbstractTransient receptor potential vanilloid 4 (TRPV4) plays a role in regulating pulmonary fibrosis (PF). While several TRPV4 antagonists including magnolol (MAG), have been discovered, the mechanism of action is not fully understood. This study aimed to investigate the effect of MAG on alleviating fibrosis in chronic obstructive pulmonary disease (COPD) based on TRPV4, and to further analyze its mechanism of action on TRPV4. COPD was induced using cigarette smoke and LPS. The therapeutic effect of MAG on COPD‐induced fibrosis was evaluated. TRPV4 was identified as the main target protein of MAG using target protein capture with MAG probe and drug affinity response target stability assay. The binding sites of MAG at TRPV4 were analyzed using molecular docking and small molecule interaction with TRPV4‐ankyrin repeat domain (ARD). The effects of MAG on TRPV4 membrane distribution and channel activity were analyzed by co‐immunoprecipitation, fluorescence co‐localization, and living cell assay of calcium levels. By targeting TRPV4‐ARD, MAG disrupted the binding between phosphatidylinositol 3 kinase γ and TRPV4, leading to hampered membrane distribution on fibroblasts. Additionally, MAG competitively impaired ATP binding to TRPV4‐ARD, inhibiting TRPV4 channel opening activity. MAG effectively blocked the fibrotic process caused by mechanical or inflammatory signals, thus alleviating PF in COPD. Targeting TRPV4‐ARD presents a novel treatment strategy for PF in COPD.
Funder
National Key Research and Development Program of China
Cited by
1 articles.
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