Piezo1 Agonist Yoda1 Induces Rapid Relaxation in Cultured Airway Smooth Muscle Cells and Bronchodilation in Mouse Models.

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mingzhi Luo, Xiangrong Zhang, Jia Guo, Rong Gu, Youyuan Qin, Kai Ni, Lei Liu, Yan Pan, Jingjing Li, Honglei Shi, Linhong Deng
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Abstract

Bronchodilators that relax airway smooth muscle cells (ASMCs) are essential for treating constrictive airway diseases such as asthma. However, the existing bronchodilators are often unable to control symptoms of severe asthmatic patients, leaving a pressing need to search for alternatives. Recent studies indicate that the transmembrane mechanosensitive channel, Piezo1 may provide a novel target for bronchodilation as it mediates ASMCs relaxation via calcium signaling and activation of large-conductance calcium-activated potassium channels (BKCa), and Piezo1 specific agonist Yoda1 has been shown to reduce cell stiffness and traction force in cultured ASMCs after 24 h incubation. Thus in this study, we further explored the potential of Yoda1 for inducing rapid ASMCs relaxation and bronchodilation. We treated either cultured ASMCs or allergen-induced mouse models of asthma with Yoda1 at various doses, and then assessed the resulting variations in cell stiffness, traction force, and molecular signaling of cultured ASMCs, as well as in airway resistance of the mouse models. We found that exposure to Yoda1 rapidly decreased cell stiffness, traction force in association with induced calcium signaling and BKCa activation in cultured ASMCs, and reduced airway resistance in methacholine-challenged mice in a dose-dependent manner. These results indicate that chemical activation of Piezo1 with specific agonist Yoda1 was indeed capable of inducing bronchodilation by relaxing ASMCs, and thus provide insights into development of Piezo1 agonist-based novel bronchodilators for treating constrictive airway disorders such as asthma.

Piezo1激动剂Yoda1诱导小鼠模型气道平滑肌细胞快速松弛和支气管扩张。
支气管扩张剂放松气道平滑肌细胞(ASMCs)是必不可少的治疗狭窄气道疾病,如哮喘。然而,现有的支气管扩张剂往往不能控制严重哮喘患者的症状,迫切需要寻找替代品。最近的研究表明,跨膜机械敏感通道Piezo1可能为支气管扩张提供了新的靶点,因为它通过钙信号传导和大电导钙活化钾通道(BKCa)介导asmc的舒张,并且Piezo1特异性激动剂Yoda1在培养asmc 24小时后被证明可以降低细胞刚度和牵引力。因此,在本研究中,我们进一步探索了Yoda1诱导asmc快速松弛和支气管扩张的潜力。我们用不同剂量的Yoda1处理培养ASMCs或过敏原诱导的哮喘小鼠模型,然后评估培养ASMCs的细胞刚度、牵引力、分子信号传导以及小鼠模型气道阻力的变化。我们发现,暴露于Yoda1能迅速降低培养ASMCs细胞的硬度、牵引力(与诱导的钙信号和BKCa激活有关),并以剂量依赖的方式降低甲基安可林刺激小鼠的气道阻力。这些结果表明,特异性激动剂Yoda1对Piezo1的化学激活确实能够通过放松ASMCs来诱导支气管扩张,从而为开发基于Piezo1激动剂的新型支气管扩张剂治疗狭窄性气道疾病(如哮喘)提供了见解。
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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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