PCSK9的激活促进了血管微生理系统的早期动脉样硬化
Jounghyun H Lee1, Kevin L Shores2, Jason J Breithaupt2
1Department of Biomedical Engineering, Columbia University, New York, New York 10032, USA.
APL bioengineering
|October 19, 2023
概括
蛋白转化酶亚提利辛/凯辛9 (PCSK9) 通过促进血管炎症驱动动动脉硬化. 用NYX-1492抑制PCSK9减少了组织工程血管模型中的炎症和单细胞粘附.
科学领域:
- 心血管生物学 心血管生物学
- 血管炎症 血管炎症
- 动脉样硬化研究 动脉样硬化研究
背景情况:
- 动脉样硬化是心血管疾病 (CVD) 的前体,由由低密度脂蛋白受体 (LDLR) 降解和血管炎症导致的proprotein转化酶亚素/kexin 9 (PCSK9) 加剧.
- PCSK9的作用超越了脂质代谢,积极促进血管内的炎症过程.
研究的目的:
- 使用血管微生理系统研究PCSK9激活和抑制对动脉样硬化发病的影响.
- 评估一种新型小分子PCSK9抑制剂在缓解PCSK9驱动的血管炎症方面的疗效.
主要方法:
- 生成的PCSK9过度表达 (P+) 或抑制 (P-) 人类诱导多能干细胞 (iPSCs).
- 分化iPSC成血管光滑肌细胞 (viSMC) 和内皮细胞 (viEC),以构建组织工程血管 (TEBV).
- 在TEBVs中在改性LDL (eLDL) 和TNF-α刺激下评估单细胞粘附和炎症标记分泌 (VCAM-1,TNF-α,IL-6),测试PCSK9抑制剂NYX-1492.
主要成果:
- 与野生类型 (WT) 或P-TEBV相比,P+ TEBVs在受到eLDL和TNF-α的挑战时表现出单细胞粘附度的增加.
- P+ viECs显示出显著的功能障碍,包括VCAM-1,TNF-α和IL-6的分泌量增加.
- NYX-1492治疗减少了P+ TEBVs中的单细胞粘附,并减少了VCAM-1和TNF-α的分泌,表明炎症减少.
结论:
- 抑制PCSK9显示出降低血管炎症的潜力,补充其降脂效应.
- 向PCSK9可能会提供增强的抗动脉样硬化益处,特别是在慢性炎症患者中.
- 开发的TEBV模型是研究动脉样硬化和查治疗化合物的宝贵平台.
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