粒体自噬
衰老
内科学
医学
内皮
内皮功能障碍
内分泌学
伊诺斯
血管生成
生物
细胞凋亡
一氧化氮合酶
自噬
一氧化氮
生物化学
作者
Li Ma,Kaifeng Li,Wenxiang Wang,Jiaheng Zhou,Ze Li,Tuo Zhang,Yunshu Wangsun,Fei Tian,Qianqian Dong,Haifeng Zhang,Wenjuan Xing
出处
期刊:Redox biology
[Elsevier]
日期:2023-06-01
卷期号:62: 102693-102693
被引量:9
标识
DOI:10.1016/j.redox.2023.102693
摘要
Vascular aging contributes to adverse changes in organ function and is a significant indicator of major cardiac events. Endothelial cells (ECs) participate in aging-provoked coronary vascular pathology. Regular exercise is associated with preservation of arterial function with aging in humans. However, the molecular basis is not well understood. The present study was aimed to determine the effects of exercise on coronary endothelial senescence and whether mitochondrial clearance regulator FUN14 domain containing 1 (FUNDC1)-related mitophagy and mitochondrial homeostasis were involved. In mouse coronary arteries, FUNDC1 levels showed gradually decrease with age. Both FUNDC1 and mitophagy levels in cardiac microvascular endothelial cells (CMECs) were significantly reduced in aged mice and were rescued by exercise training. Exercise also alleviated CMECs senescence as evidenced by senescence associated β-galactosidase activity and aging markers, prevented endothelial abnormal cell migration, proliferation, and eNOS activation in CMECs from aged mice, and improved endothelium-dependent vasodilation of coronary artery, reduced myocardial neutrophil infiltration and inflammatory cytokines evoked by MI/R, restored angiogenesis and consequently alleviated MI/R injury in aging. Importantly, FUNDC1 deletion abolished the protective roles of exercise and FUNDC1 overexpression in ECs with adeno-associated virus (AAV) reversed endothelial senescence and prevented MI/R injury. Mechanistically, PPARγ played an important role in regulating FUNDC1 expressions in endothelium under exercise-induced laminar shear stress. In conclusion, exercise prevents endothelial senescence in coronary arteries via increasing FUNDC1 in a PPARγ-dependent manner, and subsequently protects aged mice against MI/R injury. These findings highlight FUNDC1-mediated mitophagy as potential therapeutic target that prevents endothelial senescence and myocardial vulnerability.
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