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HSPA12B 通过调节 STING 降解来保护与年龄相关的内皮细胞衰老

Tingting Li¹, Peilin Zhu¹, Joseph Adams¹

¹Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.

|October 9, 2025

概括

热冲击蛋白12B (HSPA12B) 通过调节STING激活来防止与年龄相关的内皮细胞衰老和心脏功能障碍. 较低的HSPA12B加速衰老,而较高的水平提供保护,表明治疗潜力.

科学领域:

心血管生物学心血管生物学
细胞衰老细胞衰老
分子机制的分子机制

背景情况:

心血管疾病是导致死亡的主要原因,衰老是主要的危险因素.
内皮细胞 (EC) 功能障碍和衰老是与年龄相关的心肌病的核心原因.
内皮老化的分子驱动因素尚未完全理解.

研究的目的:

研究内皮特异性热冲击蛋白家族A成员12B (HSPA12B) 在与年龄相关的内皮衰老中的作用.
阐明HSPA12B通过哪些分子途径影响EC功能和血管衰老.
确定HSPA12B作为心血管功能障碍的潜在治疗标.

主要方法:

在衰老的心血管组织中评估HSPA12B表达.
利用HSPA12B缺陷和过度表达的小鼠模型来研究EC衰老和心脏功能.
研究了HSPA12B对X盒结合蛋白1 (XBP1) 路径,内分泌网膜相关降解 (ERAD) 和cGAS-STING路径的影响.
采用了针对STING和XBP1活动的药理干预措施.

主要成果:

随着年龄的增长,HSPA12B的表达减少,加速EC衰老和小鼠的心脏功能障碍.
过度表达HSPA12B可以缓解EC衰老,并保护血管衰老.
缺少HSPA12B会影响XBP1的活动,减少SEL1L和HRD1的表达,导致ERAD缺陷和STING通路激活.
药理上抑制STING或增强XBP1活性可以逆转HSPA12B缺乏引起的衰老.

结论:

在老化过程中,HSPA12B在维持内皮恒温中起着至关重要的保护作用.
HSPA12B调节了STING的XBP1介导ERAD,从而控制了EC衰老.
对于与年龄有关的心血管疾病,HSPA12B是一个有前途的治疗标.

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