血管光滑肌细胞中的分支链氨基酸催化缺陷通过mTOR过度激活驱动胸腔大动脉剖析
Liming Yu1, Tao Huang1, Jikai Zhao1
1Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China.
Free radical biology & medicine
|November 13, 2023
概括
缺陷的分支链氨基酸 (BCAA) 代谢有助于胸前大动脉剖析 (TAD),通过通过mTOR信号传递促进血管炎症和光滑肌肉细胞变化. 抑制BCKDK显示了TAD的治疗潜力.
科学领域:
- 生物化学 生物化学
- 血管生物学 血管生物学
- 代谢障碍 代谢障碍 代谢障碍
背景情况:
- 胸前大动脉解剖 (TAD) 病原包括血管光滑肌细胞 (VSMC) 的代谢重编程.
- 以前的研究集中在葡萄糖/脂肪酸代谢上,忽视了TAD中的氨基酸代谢.
研究的目的:
- 调查分支链氨基酸 (BCAA) 代谢在TAD病变发生中的作用.
- 为了确定TAD的潜在治疗点.
主要方法:
- 人类大动脉样本的生物信息分析.
- 在小鼠模型中使用BCKDK抑制剂 (BT2) 和拉帕素的体内研究.
- 使用TNF-α挑战VSMC细胞系的体外研究.
主要成果:
- 在TAD中观察到BCAA代谢受损和BCKDK表达升高.
- BT2治疗恢复了BCAA的代谢,减少了VSMC的表型切换,炎症和ROS损伤.
- mTORC1的抑制模仿了BT2的益处,而mTOR的激活则逆转了它们.
结论:
- 通过VSMC表型切换,炎症和ROS损伤通过mTOR过度激活,BCAA触媒缺陷驱动TAD.
- BCKDK和mTOR信号是TAD预防和治疗的潜在治疗点.
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