心肌细胞NOX4调节了压力心肌病症中存在的巨细胞介导炎症和腹功能障碍
Aleksandr E Vendrov1, Han Xiao2, Andrey Lozhkin1
1Frankel Cardiovascular Center, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Redox biology
|October 23, 2023
概括
压力心肌病症涉及炎症和扩张性功能障碍. 心肌细胞NOX4依赖的氧化应激通过激活巨细胞来驱动这些问题,导致纤维化和心脏功能受损.
科学领域:
- 心血管生物学 心血管生物学
- 氧化压力研究研究 氧化压力研究
- 免疫学 免疫学 免疫学
背景情况:
- 急性同情性压力会导致儿科胺过载,导致应激心肌病.
- 线粒体氧化应激与心脏功能障碍有关,但具体机制尚不清楚.
研究的目的:
- 调查心肌细胞NADPH氧化酶4 (NOX4) 依赖的线粒体氧化应激在介导应激心肌病中的炎症和透静功能障碍中的作用.
主要方法:
- 使用野生类型和心肌细胞特异性Nox4淘汰小鼠,接受异二醇 (ISO) 诱导的交感应激.
- 分析了心肌细胞NOX4表达,过氧化 (H2O2) 水平,炎症酶激活和细胞因子概况.
- 使用光谱流细胞计和t-SNE分析来表征心脏巨细胞群.
- 通过组织学和血液动力学测量评估心脏纤维细胞激活,原沉积和透静功能.
- 研究了一种选择性NOX4抑制剂 (GKT137831) 对ISO治疗小鼠的影响.
主要成果:
- 与Nox4淘汰赛小鼠相比,经过ISO处理的野生型小鼠表现出心肌细胞NOX4,H2O2,炎症酶激活和促炎细胞因子的增加.
- 野生类型的小鼠显示向亲炎性巨细胞的转变,而淘汰的小鼠在ISO后保留了更多的组织修复巨细胞.
- 在野生型心脏中,ISO诱导了心脏纤维细胞激活,纤维化和限制性透析功能障碍,在Nox4淘汰赛小鼠中减弱了效应.
- 在ISO处理的野生类型小鼠中,NOX4抑制降低了氧化应激,巨细胞透,纤维化,并保留了透缩功能.
结论:
- 心肌细胞NOX4依赖的活性氧物种 (ROS) 在应激心肌病中介导炎症和纤维化.
- 交感过度刺激会激活寄居的巨细胞,通过CM NOX4.4促进心肌炎症和腹功能障碍.
- 向NOX4可能为压力诱导的心脏功能障碍提供治疗策略.
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