ALDH1A3 在肺动脉高血压中协调新陈代谢与基因调节
Dan Li1,2,3, Ning-Yi Shao2,4,5, Jan-Renier Moonen1,2,3
1Vera Moulton Wall Center for Pulmonary Vascular Diseases (D.L., J-R.M., S.O., L.W., T.N., E.Y., M.R.), Stanford University School of Medicine, CA.
Circulation
|March 25, 2021
概括
脱酶1A3 (ALDH1A3) 协调细胞代谢和基因表达,以促进肺动脉高血压 (PAH) 的平滑肌肉细胞增殖. 针对PAH光滑肌细胞的ALDH1A3提供了一个潜在的治疗策略.
科学领域:
- 血管生物学
- 代谢调节
- 表观遗传学
背景情况:
- 平滑肌细胞的增殖导致肺动脉高血压 (PAH) 和全身血管疾病.
- 增加的葡萄糖分解是PAH中增殖性SMC表型的标志.
- 代谢变化影响染色体结构和基因表达,影响细胞功能.
研究的目的:
- 研究阿尔代脱酶家族1成员3 (ALDH1A3) 在PAH中肺动脉SMC (PASMC) 的增多和糖分代谢中的作用.
- 在小鼠模型中确定ALDH1A3是否对肺高血压的发展至关重要.
- 阐明ALDH1A3在PAH PASMC中调节基因表达和代谢的机制.
主要方法:
- 从PAH患者和对照组中对PASMC进行RNA测序.
- 评估ALDH1A3在增殖和糖解中的功能.
- 在SMC中删除Aldh1a3的转基因小鼠模型的生成.
- 核ALDH1A3活性及其对染色体修饰和基因转录的下游影响的分析.
主要成果:
- 在PAH PASMC中,ALDH1A3被上调,对其增殖性和糖解性质至关重要.
- 在小鼠中,SMC特异性删除Aldh1a3可以预防缺氧引起的肺高血压.
- 核ALDH1A3通过KAT2B在NFYA结合部位促进H3K27的乙化,促进细胞循环和代谢基因的转录.
- 在PAH PASMC中BMPR2损失上调了ALDH1A3,其转录依赖于β-catenin.
结论:
- 一个涉及ALDH1A3的代谢转录轴与PAH中SMC增殖的表观遗传和转录调节协调能量需求.
- 针对PAH SMC的ALDH1A3是一个有前途的治疗途径,可以节省内皮细胞.
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