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在巨细胞中异常的线粒体DNA合成会加剧炎症和动脉样硬化

Niranjana Natarajan¹, Jonathan Florentin¹, Ebin Johny¹

¹Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.

Nature communications

|August 26, 2024

概括

血管细胞粘附分子1 (VCAM-1) 驱动着巨细胞中的线粒体DNA合成,恶化动脉样硬化. 在巨细胞中抑制VCAM-1可减少炎症和疾病严重程度,揭示了心血管疾病进展的关键途径.

科学领域:

心血管生物学心血管生物学
免疫学免疫学免疫学
细胞的新陈代谢

背景情况:

细胞代谢显著影响炎症和动脉样硬化进展.
线粒体DNA (mtDNA) 合成在巨细胞功能和动脉样硬化中的特定作用仍然不清楚.

研究的目的:

研究线粒体DNA合成,巨细胞功能和动脉样硬化病理之间的联系.
阐明线粒体DNA合成在动脉样硬化巨细胞中受调节的分子机制.

主要方法:

斑块巨细胞的转录组学分析和动脉样硬化斑块的空间单细胞转录组学.
在人类和小鼠模型中的功能实验,包括在巨细胞中缺乏Vcam1的Apoe-/-小鼠.
评估VCAM-1表达与斑块特征和人类动脉斑块中氧化损伤的相关性.

主要成果:

血管细胞粘附分子1 (VCAM-1) 在炎症条件下触发动脉动硬化斑块巨细胞中线粒体DNA (mtDNA) 合成.
VCAM-1激活C/EBPα,导致Cmpk2和Pgc1a的表达增加,促进mtDNA合成和STING介导的炎症.
在巨细胞中缺乏VCAM-1的小鼠表现出降低了动脉样硬化和炎症;VCAM-1表达与人类的斑块严重程度和DNA损伤相关.

结论:

巨细胞VCAM-1通过VCAM-1-C/EBPα-mtDNA合成-STING通路促进炎症和动脉动脉生成起着至关重要的作用.
这一途径代表了一种自我加剧的机制,有助于导致心血管疾病.
向巨细胞VCAM-1可能为动脉样硬化提供治疗策略.

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