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- Title
Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission.
- Authors
Ma, Dong; Zheng, Bin; Liu, He-liang; Zhao, Yong-bo; Liu, Xiao; Zhang, Xin-hua; Li, Qiang; Shi, Wei-bo; Suzuki, Toru; Wen, Jin-kun
- Abstract
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. Down-regulation of Klf5, an essential transcriptional factor of cardiovascular remodeling, in vascular smooth muscle cells is correlated with vascular senescence and rupture of abdominal aortic aneurysm. This effect is mediated by increased mitochondrial fission and production of reactive oxygen species.
- Subjects
AORTIC rupture; REACTIVE oxygen species; CELLULAR aging; VASCULAR smooth muscle; ANGIOTENSIN II
- Publication
PLoS Biology, 2020, Vol 18, Issue 8, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000808