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通过基因变异调节的内皮KSR2通过AMPKα1稳定来保护动脉样硬化
Ming Liu1, Xiangrui Fu1, Hui Zhang1
1National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Theranostics
|December 22, 2025
概括
一种靠近KSR2 (Ras 2的激酶抑制剂) 的基因变异通过影响内皮细胞中的KSR2表达来影响冠状动脉疾病风险. 这项研究揭示了KSR2通过稳定AMPK来保护动脉样硬化,为CAD提供了新的治疗点.
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
- 生物化学 生物化学
背景情况:
- 在KSR2基因附近的单核酸多态 (SNP) rs11830157与冠状动脉疾病 (CAD) 风险有关,但其功能作用尚不清楚.
- 了解连接KSR2与动脉样硬化的分子机制对于开发有效的CAD预防和治疗策略至关重要.
研究的目的:
- 为了研究rs11830157多态性对动脉样硬化发展的影响.
- 阐明KSR2影响动脉样硬化的分子机制.
主要方法:
- 使用双露西法酶记者测定,ChIP,EMSA和CRISPR/Cas9基因编辑来研究SNP rs11830157.
- 采用了全球KSR2淘汰赛小鼠,KSR2/Apoe双淘汰赛小鼠和AAV9-介导的内皮KSR2过度表达模型.
- 分析了人类和小鼠动脉样硬化斑块中的KSR2表达.
主要成果:
- 鉴定SNP rs12822146,与rs11830157的结合不平衡,通过XBP1s结合来调节KSR2的表达.
- 在动脉样硬化斑块内的内皮细胞中发现显著降低了KSR2表达.
- 证明内皮细胞KSR2通过抑制炎症和亡来保护动脉样硬化.
- 从机制上讲,KSR2通过与CRBN竞争与AMPKα1结合,从而激活AMPK路径来抑制AMPKα1的降解.
结论:
- 确定了rs12822146-KSR2-动脉样硬化轴,为SNP与CAD的关联提供了分子解释.
- 通过AMPK通路激活,展示了内皮KSR2对动脉样硬化的保护作用.
- 强调了针对KSR2-AMPK途径用于CAD预防和治疗的潜力.
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