化 perhexiline衍生物减弱了肺动脉高血压中的血管扩散,平滑肌肉细胞

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Published on: February 11, 2017

Kayleigh Griffiths¹, Roger J Grand², Ian Horan³

¹Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.

Vascular pharmacology

|June 20, 2024

概括

珀赫西林及其衍生物FPER-1在肺动脉高血压 (PAH) 平滑肌细胞中逆转了华堡生理学,通过激活酸脱酶 (PDH) 减少了增殖,并增强了线粒体呼吸,而不会诱导亡.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
药理学药理学是指药理学的学科.

背景情况:

肺动脉高血压 (PAH) 的特点是肺动脉光滑肌细胞 (PASMCs) 的增多和减少细胞灭亡.
这种细胞行为与减少的酸盐脱酶 (PDH) 活性有关,导致氧化酸化的减少和有氧糖解的增加 (Warburg 效应).
珀赫西林是一种卡尼丁棕转移酶-1 (CPT1) 抑制剂,增加了PDH活性,但由于CYP2D6代谢而具有可变的药理动力学,造成毒性风险.

研究的目的:

为了研究fermexiline和一种新型化衍生物 (FPER-1) 对PAH患者PASMC中的PDH流量的影响.
确定这些化合物是否可以逆转PAH PASMCs中观察到的华堡效应.
评估fermexiline和FPER-1在缓解PAH相关的细胞功能障碍方面的治疗潜力.

主要方法:

在PAH PASMC中证实增加了扩散,AKT/ERK酸化和PDH-E1α酸化,这表明了华堡效应.
用不同度的家庭西林和FPER-1治疗的PAH PASMCs.
评估了细胞增殖,细胞亡 (caspase 3/7活性),PDH活性 (PDH-E1α的脱化),糖解和线粒体呼吸 (海马分析).

主要成果:

珀赫西林和FPER-1显著减弱了PAH PASMC的扩散,以度依赖的方式.
这两种化合物都抑制了AKT酸化,但没有影响ERK通路.
珀赫西林和FPER-1显著激活PDH,降低糖解,并上调线粒体呼吸,而不会诱导PAH PASMCs中的亡.

结论:

珀赫西林和FPER-1证明了在人类PAH PASMC中逆转华堡生理学的能力.
这些化合物激活PDH,减少糖解,增强线粒体呼吸,从而减少细胞增殖.
西林和FPER-1通过向PASMC中的关键代谢失调,显示出作为PAH治疗剂的前景.

关键词:

佩雷克西林 (Perhexiline) 是一种药物.肺动脉高血压是肺动脉高血压.肺动脉平滑肌肉细胞肺动脉平滑肌肉细胞皮鲁酸盐脱酶的使用方法

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