Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation
Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation
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DOI：
10.1164/rccm.200802-320oc
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发表时间：
2009-02-15
影响因子：
24.7
通讯作者：
Hunninghake, Gary W.
中科院分区：
文献类型：
--
作者：
Nyunoya, Toru;Monick, Martha M.;Hunninghake, Gary W.
基本原理。沃纳氏综合征是一种遗传性疾病，由于编码RecQ解旋酶家族成员的基因发生了功能丧失突变，导致过早衰老。维尔纳氏综合症和吸烟都会加速衰老。没有研究检验过香烟对维尔纳氏综合征蛋白的影响。目的：探讨沃纳氏综合征蛋白在香烟诱导的细胞衰老中的作用。方法：在肺气肿患者分离的成纤维细胞中测量细胞衰老和维尔纳综合征蛋白的数量，并与年龄匹配的非吸烟者进行比较。在体外实验中，香烟烟雾对人肺原代成纤维细胞和上皮细胞中维尔纳综合征蛋白、功能和衰老的影响也进行了评估。测量和主要结果：从肺气肿患者分离的培养肺成纤维细胞表现出衰老表型，并伴有维尔纳综合征蛋白的减少。香烟烟雾提取物可降低培养成纤维细胞和上皮细胞中维尔纳综合征蛋白含量。沃纳氏综合征蛋白缺乏的成纤维细胞更容易受到香烟引起的细胞衰老和细胞迁移障碍的影响。相反，外源性过表达维尔纳综合征蛋白会减弱香烟烟雾的影响。结论：吸烟通过下调Werner's综合征蛋白介导细胞衰老和细胞迁移功能障碍。挽救维尔纳氏综合征蛋白下调可能是吸烟相关疾病的潜在治疗靶点。
Rationale. Werner's syndrome Is a genetic disorder that causes premature aging due to loss-of-function mutations In a gene encoding a member of the RecQ helicase family. Both Werner's syndrome and cigarette smoking accelerate aging. No studies have examined the effect of cigarette smoke on Werner's syndrome protein.Objectives: To Investigate the role of Werner's syndrome protein In cigarette smoke-induced cellular senescence.Methods: Cellular senescence and amounts of Werner's syndrome protein were measured In fibroblasts Isolated from patients with emphysema and compared with age-matched nonsmokers. The in vitro effects of cigarette smoke on amounts of Werner's syndrome protein, function, and senescence were also evaluated In primary human lung fibroblasts and epithelial cells.Measurements and Main Results: Cultured lung fibroblasts Isolated from patients with emphysema exhibited a senescent phenotype accompanied by a decrease In Werner's syndrome protein. Cigarette smoke extract decreased Werner's syndrome protein In cultured fibroblasts and epithelial cells. Werner's syndrome protein-deficient fibroblasts were more susceptible to cigarette smoke-induced cellular senescence and cell migration impairment. In contrast, exogenous overexpression of Werner's syndrome protein attenuated the cigarette smoke effects.Conclusions: Cigarette smoke induces cellular senescence and cell migration impairment via Werner's syndrome protein down-regulation. Rescue of Werner's syndrome protein down-regulation may represent a potential therapeutic target for smoking-related diseases.