TMEM175通过mTORC1-lysosomal轴调制来拯救心脏病发作后的心脏功能障碍
Chen Chen1,2,3, Han Lou1,2,3, An-Ge Hu1,2,3
1State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy; and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.
Acta pharmacologica Sinica
|February 25, 2026
概括
lysosomal跨膜蛋白175 (TMEM175) 通过恢复 lysosomal 功能和改善细胞降解来保护心肌梗塞 (MI) 后的心脏. TMEM175 缺乏会使心脏损伤恶化,并损害自.
科学领域:
- 心血管生物学 心血管生物学
- 细胞生物学 细胞生物学
- 分子医学是分子医学.
背景情况:
- lysosomal 功能障碍有助于心肌梗塞 (MI) 中心肌细胞损伤.
- lysosomal跨膜蛋白175 (TMEM175) 在心脏病发作后心脏功能障碍中的作用尚不清楚.
- TMEM175对于维持 lysosomal 稳态至关重要.
研究的目的:
- 为了研究TMEM175在心脏功能障碍中的作用.
- 阐明TMEM175影响 lysosomal 功能和心脏保护的分子机制.
主要方法:
- 在体内和体外使用TMEM175.5的功能增减模型.
- 评估心脏损伤标志物,心脏病发作大小和心脏病发作后的原沉积.
- 评估了 lysosomal 功能,包括生物发生,pH,酶活性和自相流动.
- 研究了TMEM175在低氧应激下对mTORC1酸化和TFEB核转位的影响.
主要成果:
- TMEM175过度表达在心脏病发作模型中显示出显著的心脏保护作用,减少了心脏病发作的大小和心肌损伤.
- 在TMEM175过度表达的情况下,观察到恢复了 lysosomal 功能,正常化了 pH,增强了酶活动,并改善了自流.
- TMEM175倒置加剧了心脏病理和溶酶体功能障碍,特别是在低氧条件下.
- 从机制上讲,MI诱导的TMEM175减少导致mTORC1酸化增加和抑制TFEB转位,损害了溶解体基因调节.
结论:
- TMEM175通过维护 lysosomal 功能和自,在心脏病发作后的心脏中发挥着关键的保护作用.
- 恢复TMEM175水平可以逆转MI诱导的溶酶体功能障碍并改善心脏损伤.
- TMEM175缺乏症通过mTORC1/TFEB通路失调加剧心脏损伤.
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