在达沙替尼与肺动脉高血压和内皮细胞功能障碍相关的KCNK3功能障碍的作用
Hélène Le Ribeuz1,2, Anaïs Saint-Martin Willer1,2, Benoit Chevalier3
1Paris-Saclay University, Faculty of Medecine, Le Kremlin-Bicêtre, France.
American journal of respiratory cell and molecular biology
|March 28, 2024
概括
一种KCNK3基因变异导致达沙替尼布诱导的肺动脉高血压 (PAH). 达沙替尼减少了KCNK3的功能和表达,导致内皮功能障碍和PAH中的光滑肌肉细胞变化.
科学领域:
- 心血管生物学 心血管生物学
- 分子医学是分子医学.
- 细胞生理学 细胞生理学
背景情况:
- 肺动脉高血压 (PAH) 是一种严重的疾病,与达沙替尼 (dasatinib) 等药物和遗传因素有关.
- 与达沙替尼布相关的PAH的确切机制仍然不完全理解.
- 通道基因KCNK3与心血管功能有关.
研究的目的:
- 研究KCNK3基因变异在达沙替尼与PAH相关的作用.
- 确定达沙替尼对KCNK3功能和表达的影响.
- 阐明PAH中KCNK3功能障碍背后的细胞机制.
主要方法:
- 在一个PAH患者中确定了KCNK3变体.
- 利用补丁电生理学来评估KCNK3的功能.
- 在人类肺动脉光滑肌细胞 (hPASMCs) 和肺内皮细胞 (hPECs) 中进行了KCNK3淘汰实验.
- 分析了细胞迁移,线粒体功能和ATP生产.
- 使用质谱和近距离标记确定了KCNK3互动原子.
主要成果:
- 鉴定到的KCNK3变种表现出功能丧失.
- 达沙提尼布暴露降低了KCNK3的功能和表达,导致肺动脉收缩.
- 在hPASMCs中KCNK3的淘汰诱导了线粒体脱极化和向糖解转移.
- 达沙替尼或KCNK3 knockdown减少了hPECs中的洞穴.
- KCNK3的淘汰破坏了hPEC的迁移,增殖和体外管体生成.
- 在KCNK3互动组中,发现了与各种细胞蛋白的相互作用.
结论:
- 一种新的致病性KCNK3变体与达沙替尼布诱导的PAH有关.
- 达沙替尼降低KCNK3的调节,将药物暴露与PAH中KCNK3功能障碍联系起来.
- 丧失KCNK3信号传递有助于肺内皮功能障碍和PAH中的光滑肌肉细胞代谢变化.
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