A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.
A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.
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DOI：
10.1371/journal.pone.0102186
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Minamino T
中科院分区：
文献类型：
--
作者：
Ito TK;Yokoyama M;Yoshida Y;Nojima A;Kassai H;Oishi K;Okada S;Kinoshita D;Kobayashi Y;Fruttiger M;Aiba A;Minamino T
动脉粥样硬化的危险因素加速血管内皮细胞的衰老，并通过诱导血管炎症促进动脉粥样硬化的形成。内皮衰老的标志是促炎基因的持续上调。我们确定了CDC 42信号传导作为与内皮衰老相关的慢性炎症介质。抑制CDC 42或NF-κB信号转导减弱了衰老人内皮细胞中促炎基因的持续上调。p53/p21通路（衰老的关键介质）的内皮特异性激活也导致小鼠中促炎分子的上调，这被内皮细胞中Cdc 42缺失逆转。同样，内皮特异性Cdc 42缺失显著减弱了动脉粥样硬化小鼠的慢性炎症和斑块形成。抑制NF-κB可抑制急性炎症中的促炎反应，而Cdc 42缺失的影响不太明显。cdc-42基因的敲除显著下调了促炎基因的表达，并使炎症增强的突变蠕虫的寿命恢复正常。这些发现表明，CDC 42通路与衰老相关的炎症密切相关，可能是年龄相关疾病患者慢性炎症的治疗靶点，而不会损害宿主防御。
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.
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