在光滑肌肉细胞中缺乏心氨酸会通过HSF1驱动的胆固醇生物合成和PERK激活来增加动脉样硬化
Suravi Majumder1, Abhijnan Chattopadhyay1, Jamie M Wright1
1Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, and.
JCI insight
|November 8, 2023
概括
在光滑肌肉细胞中缺乏心氨酸 (PCNT) 会通过激活细胞应激和胆固醇合成来驱动动动脉硬化. 类药物可以降低冠状动脉疾病 (CAD) 风险在小脑骨质疏松性原始矮体 II 型 (MOPDII) 患者.
科学领域:
- 心血管生物学 心血管生物学
- 分子遗传学 分子遗传学
- 代谢疾病 代谢疾病
背景情况:
- 微脑骨质可塑性原始矮体II型 (MOPDII) 是一种与周心素 (PCNT) 变异相关的遗传疾病.
- 早期冠状动脉疾病 (CAD) 是MOPDII患者的一种严重并发症,其组织病理学揭示了广泛的动脉样硬化.
研究的目的:
- 调查MOPDII中动脉样硬化背后的分子机制.
- 确定PCNT缺陷在光滑肌细胞 (SMCs) 在动脉生成中的作用.
- 评估HMG-CoA减少酶 (HMGCR) 抑制的治疗潜力.
主要方法:
- 使用了一种小鼠模型,该小鼠模型具有SMC特定的Pcnt缺乏 (PcntSMC-/-) 和超脂血症.
- 分析了动脉样硬化斑块负担,血清脂质水平和SMC表型.
- 研究了热冲击因子1 (HSF1) 和胆固醇生物合成途径的激活.
- 评估了HMGCR抑制剂普拉瓦斯塔丁对斑块发育的影响.
主要成果:
- 在SMC中PCNT缺乏症显著增加了超脂症小鼠的动脉样硬化斑块负担.
- 损失PCNT诱导HSF1激活,上调HMGCR和胆固醇生物合成.
- 增加胆固醇合成增强了PERK信号和SMC表型调制.
- 在PcntSMC-/-小鼠中,普拉瓦斯塔丁治疗降低了SMC调节和斑块负担.
结论:
- 在SMC中PCNT缺乏促进动脉样硬化通过细胞应激,HSF1激活和增强胆固醇生物合成,独立于基线胆固醇水平.
- 用他类药物向HMGCR通路可能是减轻MOPDII患者CAD风险的可行策略.
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