减少性压力会导致未解决的ER压力和蛋白质毒性心肌病
Sini Sunny1, Rajesh Kumar Radhakrishnan1, Asokan Devarajan2
1Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Redox biology
|July 29, 2025
概括
慢性减少性压力通过损害ER平衡和蛋白质质量控制来破坏心脏功能. 这导致了病态的心脏重塑和腹功能障碍,特别是在高表达的转基因小鼠心脏中.
科学领域:
- 心血管生物学 心血管生物学
- 细胞应激反应的应激反应
- 分子心脏病学分子心脏病学
背景情况:
- 构成性Nrf2激活的慢性减缓性压力 (cRS) 会导致病态的心脏重塑和腹功能障碍.
- 转录组分析揭示了ER相关的基因失调和在cRS下展开的蛋白质反应 (UPR) 激活.
研究的目的:
- 研究慢性减少性压力对ER恒温,蛋白质稳定和心脏功能的影响.
- 阐明转基因小鼠模型中cRS诱导的心脏病理背后的分子机制.
主要方法:
- 转基因 (TG) 小鼠心脏的转录组分析 (RNA-seq).
- 评估未折叠蛋白质响应 (UPR) 激活和ER功能.
- 评估蛋白质稳定,包括无处不在,蛋白质酶活性和蛋白质聚合.
- 斑点跟踪回声心脏学 (STE) 用于心脏功能分析.
主要成果:
- cRS 干扰ER基因表达,激活UPR,并导致氧化还原失衡 (谷氨升高,ROS降低).
- 蛋白质稳定性受损,导致蛋白质错折,ER扩张,蛋白质聚合和蛋白质质量控制 (PQC) 不足.
- 观察到心肌失调,渐进性应变异常,缩/放缩功能障碍,与蛋白质毒性负担相关.
结论:
- 慢性还原性压力会破坏ER平衡,并诱导蛋白质毒性,损害心脏结构和功能.
- 不适应性心脏重塑得到了cRS中Nogo/Reticulon4上调的支持.
- 这些发现凸显了慢性RS对心脏的有害影响,特别是在高转基因表达条件下.
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