雌激素和Cyp1b1通过依赖于乌比基的机制调节肺高血压中的Pparγ
Jingyuan Chen1,2, Xinping Chen1,3, Vineet Agrawal4
1Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USA.
女性性别增加了肺动脉高血压 (PAH) 的风险. 这项研究揭示了雌激素和Cyp1b1酶水平如何影响Pparγ,这是一种关键蛋白质,影响能量代谢,并可能导致女性的PAH发展.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 心血管研究研究心血管研究
背景情况:
- 女性性别是I组肺动脉高血压 (PAH) 的重要危险因素,其机制尚不清楚.
- 雌激素代谢酶P450 1B1 (Cyp1b1) 的低表达与PAH疾病透率相关,特别是在女性中.
- 以前的研究表明,在PAH模型中降低的氧酶增殖器激活受体玛 (Pparγ) 水平被雌激素阻塞逆转.
研究的目的:
- 研究雌激素,Cyp1b1和细胞能量代谢之间的复杂相互作用.
- 阐明Cyp1b1在PAH发病过程中的作用,同时考虑依赖雌激素和独立途径.
- 探索PAH中雌激素-Cyp1b1-Pparγ轴内的潜在治疗点.
主要方法:
- 用雌激素或针对Cyp1b1的siRNA处理的细胞培养实验,以评估Pparγ蛋白水平和辅因子.
- 海马XF分析评估Cyp1b1敲击对细胞呼吸的影响,特别是脂肪酸氧化.
- 在高脂肪饮食和不含高脂肪饮食的情况下,在Cyp1b1淘汰赛 (KO) 和野生型 (WT) 鼠的内皮细胞和肺部上进行RNA测序 (RNA-seq).
主要成果:
- 雌激素和Cyp1b1 knockdown降低了Pparγ蛋白水平,影响了Pparγ辅因子和细胞呼吸,这与ubiquitination有关.
- 在高脂肪饮食中,Cyp1b1 KO小鼠表现出较低的Pparγ水平,并发展出轻度肺高血压.
- RNA-seq揭示了改变的脂质代谢,细胞因子信号传递和血管活性途径,在Cyp1b1 KO小鼠肺部增加了昼夜节律基因改变.
结论:
- Cyp1b1在调节Pparγ水平和能量代谢方面发挥着至关重要的作用,有助于PAH的发展.
- 针对Pparγ泛化的干预措施可能为雌激素和Cyp1b1介导的PAH提供治疗策略.
- Cyp1b1对PAH的影响是复杂的,涉及雌激素效应和影响脂质代谢和昼夜节律的独立途径.
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