生物
线粒体分裂
细胞生物学
血管平滑肌
衰老
转录因子
活性氧
线粒体
线粒体融合
细胞凋亡
基因敲除
线粒体DNA
内分泌学
基因
遗传学
平滑肌
作者
Dong Ma,Bin Zheng,Heliang Liu,Yongbo Zhao,Xiao Liu,Xinhua Zhang,Qiang Li,Wanying Shi,Toru Suzuki,Jin‐Kun Wen
出处
期刊:PLOS Biology
[Public Library of Science]
日期:2020-08-20
卷期号:18 (8): e3000808-e3000808
被引量:46
标识
DOI:10.1371/journal.pbio.3000808
摘要
Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.
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