PLoS biology, 2020-08, Vol.18 (8), p.e3000808-e3000808
2020
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- Autor(en) / Beteiligte
- Titel
- Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission
- Ist Teil von
- PLoS biology, 2020-08, Vol.18 (8), p.e3000808-e3000808
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1545-7885, 1544-9173eISSN: 1545-7885DOI: 10.1371/journal.pbio.3000808Titel-ID: cdi_plos_journals_2443589285
- Format
- –
- Schlagworte
- Abdomen, Age, Age related diseases, Aged, Aneurysms, Angiotensin, Angiotensin II, Angiotensin II - genetics, Angiotensin II - metabolism, Angiotensin II - pharmacology, Animals, Aorta, Aorta - diagnostic imaging, Aorta - metabolism, Aorta - pathology, Aortic Aneurysm, Abdominal - diagnostic imaging, Aortic Aneurysm, Abdominal - genetics, Aortic Aneurysm, Abdominal - metabolism, Aortic Aneurysm, Abdominal - pathology, Apoptosis, Biochemistry, Biology and Life Sciences, Cell cycle, Cellular Senescence - drug effects, Coronary vessels, Depletion, Echocardiography, Education, Endothelial Cells - metabolism, Endothelial Cells - pathology, Eukaryotic Translation Initiation Factor 5A, Female, Fission, Funding, GTP Phosphohydrolases - genetics, GTP Phosphohydrolases - metabolism, Heart surgery, Humans, Initiation factor eIF-5A, Kruppel-Like Transcription Factors - deficiency, Kruppel-Like Transcription Factors - genetics, Laboratories, Male, Medicine and Health Sciences, Metabolism, Mice, Mice, Knockout, Mitochondria, Mitochondria - metabolism, Mitochondria - pathology, Mitochondrial Dynamics - drug effects, Molecular biology, Muscles, Oxidative stress, Peptide Initiation Factors - deficiency, Peptide Initiation Factors - genetics, Primary Cell Culture, Promoter Regions, Genetic, Protein Binding, Public health, Reactive oxygen species, Reactive Oxygen Species - metabolism, Research and Analysis Methods, RNA-Binding Proteins - genetics, Senescence, Smooth muscle, Statistical analysis, Vascular diseases, Vascular endothelial growth factor, Visualization