线粒体酸感应离子通道1a缺乏导致肺动脉平滑肌细胞中的线粒体功能障碍
bioRxiv : the preprint server for biology
|September 26, 2025
概括
肺动脉平滑肌细胞中线粒体ASIC1a的损失通过损害线粒体功能和促进亡耐药性,有助于肺高血压. 恢复mtASIC1a可以逆转这些影响.
科学领域:
- 心血管生物学 心血管生物学
- 线粒体生物学 线粒体生物学
- 肺高血压的病理生理学
背景情况:
- 肺高血压 (PH) 涉及肺动脉重塑,细胞增殖和细胞亡抵抗.
- 酸感应离子通道1a (ASIC1a) 对于慢性缺氧 (CH) 诱导的PH至关重要,在肺动脉光滑肌细胞 (PASMC) 中重新分布到血中.
- 神经元中的线粒体ASIC1a (mtASIC1a) 与氧化应激和亡有关;其在PASMC中的作用尚未探索,但可能与PH相关.
研究的目的:
- 调查mtASIC1a在调节CH诱导PH期间PASMCs中线粒体平衡的作用.
- 确定mtASIC1a的丧失是否有助于线粒体功能障碍和PH的亡抵抗.
- 评估恢复mtASIC1a.a的治疗潜力.
主要方法:
- 评估了PASMC和控制和CH大鼠的肺动脉中的mtASIC1a定位.
- 从CH大鼠和Asic1a淘汰小鼠的PASMC中评估了线粒体膜潜力 (Δψm),线粒体Ca2+,超氧化物水平,线粒体和分裂的caspase-3.
- 利用传输电子显微镜进行线粒体形态分析.
- 在CH大鼠PASMC中使用lentivirus恢复mtASIC1a表达.
主要成果:
- CH降低了PASMC和肺动脉中的mtASIC1a定位.
- 来自CH大鼠和Asic1a淘汰赛小鼠的PASMCs显示了Δψm超极化,线粒体Ca2+和超氧化物升高,线粒体细胞衰变受损,并减少了分裂的caspase-3.
- 线粒体表现出形态变化 (增加大小,减少面比,减少数量) 没有改变的融合/裂变蛋白.
- 透视性mtASIC1a恢复使Δψm正常化,并恢复了caspase-3裂纹.
结论:
- mtASIC1a是PASMCs中线粒体功能的新型调节剂.
- 在CH中失去mtASIC1a促进了PASMC线粒体功能障碍 (Δψm超极化,线粒细胞衰变受损) 和亡抵抗.
- 恢复mtASIC1a具有通过改善线粒体健康来改善PH的治疗潜力.
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