在临床前的肺动脉高血压中,Sine oculis homeobox 1驱动内皮功能障碍
Ting Liu1,2,3, Wei Zhou4, Cheng Fang5
1Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
Science translational medicine
|February 4, 2026
概括
鼻眼1 (SIX1) 驱动肺动脉高血压 (PAH) 通过促进内皮功能障碍. 用扎菲尔卢卡斯特抑制SIX1对治疗PAH和相关的血管改造有希望.
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.
- 肺高血压研究 肺高血压研究
背景情况:
- 内皮功能障碍是血管改造和肺动脉高血压 (PAH) 的核心.
- 视线内1 (SIX1) 是一个转录因子,在胚胎发育后通常会降低调节,在成年人血管健康中起着不为人知的作用.
- 以前的研究表明,Six1对肺血管发育至关重要.
研究的目的:
- 调查SIX1在肺动脉高血压 (PAH) 病变发生中的作用.
- 探索SIX1作为PAH的潜在治疗点.
- 阐明SIX1在PAH中对内皮功能障碍作出贡献的分子机制.
主要方法:
- 从PAH患者和PH患者的肺动脉中SIX1表达的分析.
- 在低氧条件下,在体外研究中使用siRNA使SIX1在内皮细胞中沉默.
- 在体内研究涉及内皮特异性Six1淘汰和过度表达的小鼠模型,和zafirlukast治疗PH的老鼠模型.
- 多组学分析,以识别SIX1目标和下游信号通路.
主要成果:
- 在患有PAH和异常性肺纤维化相关PH的患者的肺动脉中,SIX1表达升高.
- 在体外,SIX1沉默抑制了缺氧诱导的内皮功能障碍 (增殖,EMT,内皮蛋白-1释放).
- 内皮特异性Six1淘汰会改善小鼠的PH表型,而过度表达会诱导自发的PH.
- 扎菲尔卢卡斯特抑制了SIX1活性,抑制了内皮功能障碍,并逆转了老鼠的已建立的PH.
- SIX1调节MAST4转录,该转录可酸化MAPK1/3,从而导致内皮功能障碍.
结论:
- 在PAH中SIX1被上调,并作为内皮功能障碍和肺血管重塑的关键驱动因素.
- 针对SIX1,例如用zafirlukast,代表了对PAH的有希望的治疗策略.
- SIX1-MAST4-MAPK1/3轴是PAH中内皮功能障碍的关键途径.
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