期刊
PLOS ONE
卷 9, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0102186
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology
- GCOE program at Chiba University
- Japan Prize Foundation
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ono Medical Research Foundation
- Uehara Memorial Foundation
- Daiichi-Sankyo Foundation of Life Science
- NOVARTIS Foundation for the Promotion Science
- Japan Diabetes Foundation
- Mitsui Life Social Welfare Foundation
- Naito Foundation
- Japanese Society of Anti-aging Medicine
- Life Science Foundation of Japan
- SENSHIN Medical Research Foundtion
- Takeda Science Foundation
- Mitsubishi Pharma Research Foundation
- MRC [G0501711] Funding Source: UKRI
- Medical Research Council [G0501711] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [24390195, 25670382, 26115008] Funding Source: KAKEN
Risk factors for atherosclerosis accelerate the senescence of vascular endothelial cells and promote atherogenesis by inducing vascular inflammation. A hallmark of endothelial senescence is the persistent up-regulation of pro-inflammatory genes. We identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence. Inhibition of CDC42 or NF-kappa B signaling attenuated the sustained up-regulation of pro-inflammatory genes in senescent human endothelial cells. Endothelium-specific activation of the p53/p21 pathway, a key mediator of senescence, also resulted in up-regulation of pro-inflammatory molecules in mice, which was reversed by Cdc42 deletion in endothelial cells. Likewise, endothelial-specific deletion of Cdc42 significantly attenuated chronic inflammation and plaque formation in atherosclerotic mice. While inhibition of NF-kappa B suppressed the pro-inflammatory responses in acute inflammation, the influence of Cdc42 deletion was less marked. Knockdown of cdc-42 significantly down-regulated pro-inflammatory gene expression and restored the shortened lifespan to normal in mutant worms with enhanced inflammation. These findings indicate that the CDC42 pathway is critically involved in senescence-associated inflammation and could be a therapeutic target for chronic inflammation in patients with age-related diseases without compromising host defenses.
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