title: A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.
abstract: 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-κB 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-κB 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.
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Takashi K
authors: TK
authors: Ito
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Masataka
authors: M
authors: Yokoyama
authors: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Yohko
authors: Y
authors: Yoshida
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Aika
authors: A
authors: Nojima
authors: Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Hidetoshi
authors: H
authors: Kassai
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Kengo
authors: K
authors: Oishi
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Sho
authors: S
authors: Okada
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Daisuke
authors: D
authors: Kinoshita
authors: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors: Yoshio
authors: Y
authors: Kobayashi
authors: Institute of Ophthalmology, University College London, London, United Kingdom.
authors: Marcus
authors: M
authors: Fruttiger
authors: Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Atsu
authors: A
authors: Aiba
authors: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; PRESTO, Japan Science and Technology Agency, Saitama, Japan.
authors: Tohru
authors: T
authors: Minamino
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008136:Longevity / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D020764:cdc42 GTP-Binding Protein