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A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.

PloS one (2014-07-25)
Takashi K Ito, Masataka Yokoyama, Yohko Yoshida, Aika Nojima, Hidetoshi Kassai, Kengo Oishi, Sho Okada, Daisuke Kinoshita, Yoshio Kobayashi, Marcus Fruttiger, Atsu Aiba, Tohru Minamino
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
4-Hydroxytamoxifen, ≥70% Z isomer (remainder primarily E-isomer)
Supelco
4-Hydroxytamoxifen, analytical standard, (E) and (Z) isomers (50:50)
Supelco
4-Hydroxytamoxifen, (E) and (Z) isomers (50:50), analytical standard