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内皮的γ-protocadherins抑制KLF2和KLF4,从而促进动脉样硬化

Divyesh Joshi¹, Brian G Coon¹, Raja Chakraborty¹

¹Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.

Nature cardiovascular research

|September 4, 2024

概括

聚合的玛-protocadherins抑制在动脉样硬化中的保护性KLF2/KLF4基因. 在内皮细胞中准这些抑制剂为动脉样硬化心血管疾病 (ASCVD) 提供了一种新的治疗策略.

科学领域:

心血管生物学心血管生物学
分子医学是分子医学.
血管炎症血管炎症

背景情况:

动脉样性心血管疾病 (ASCVD) 是一个主要的全球健康问题.
内皮KLF2和KLF4转录因子,由层切应力诱导,赋予血管保护ASCVD.
识别这些保护性通路的新型调节剂对于治疗开发至关重要.

研究的目的:

在ASCVD的背景下,确定调节KLF2和KLF4的新分子标.
调查聚合的玛-protocadherins在内皮功能障碍和ASCVD病变的作用.
为了评估针对ASCVD治疗的向玛-protocadherins的治疗潜力.

主要方法:

作为KLF2和KLF4的调节剂,研究了聚类的玛-原蛋白.
进行了涉及蛋白质裂变,核转位和蛋白质-蛋白质相互作用 (玛-原蛋白和Notch细胞内域) 的机制研究.
在ASCVD小鼠模型中利用基因删除和抗体阻断,并对人类ASCVD内皮进行分析.

主要成果:

集群的玛-protocadherins被确定为强大的抑制KLF2和KLF4,在ASCVD上调.
玛-原托卡德林裂变导致其细胞内域的核转移,抑制了Notch信号传递.
基因删除或抗体阻断的玛-protocadherins授予保护ASCVD在小鼠,而不会损害免疫防御.

结论:

集群的玛-protocadherins通过抑制保护性KLF2/KLF4.4驱动ASCVD血管炎症的关键机制.
向玛-原蛋白达林为ASCVD提供了一个有前途的内皮细胞中心治疗策略.
这种方法避免了全身免疫抑制,为当前治疗方法提供了更安全的替代方案.

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