Age-dependent increase in c-fos activity and cyclin A expression in vascular smooth muscle cells. A potential link between aging, smooth muscle cell proliferation and atherosclerosis.
Age-dependent increase in c-fos activity and cyclin A expression in vascular smooth muscle cells. A potential link between aging, smooth muscle cell proliferation and atherosclerosis.
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DOI：
10.1016/s0008-6363(99)00385-5
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发表时间：
2000-03
影响因子：
10.8
通讯作者：
A. Rivard;N. Principe;V. Andrés
中科院分区：
文献类型：
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作者：
A. Rivard;N. Principe;V. Andrés
目的：衰老是指机体达到最大繁殖能力后，生物学功能逐渐退化的过程，通常与大多数细胞类型增殖能力的下降有关。然而，在某些病理情况下，如动脉粥样硬化和再狭窄，老化已被证明与血管成形术后血管平滑肌细胞（VSMC）增殖和新生内膜病变形成的较高水平。在本研究中，我们调查了潜在的机制参与年龄依赖性的增加VSMC proliferation.Methods和结果：VSMCs的原代培养分离年轻（6-8个月大）和老年（4-5岁）新西兰兔。细胞计数和流式细胞仪分析的结果与老年VSMCs细胞周期缩短一致。血清刺激的细胞中的蛋白质印迹分析显示，在老年VSMCs与年轻VSMCs的细胞周期蛋白A和细胞周期蛋白依赖性激酶2蛋白的水平显着增加。与此形成鲜明对比的是，细胞周期蛋白E在血管平滑肌细胞中的表达不受衰老的影响。瞬时转染试验显示，从人细胞周期蛋白A启动子转录的年龄依赖性增加。平行研究表明，与细胞周期蛋白A启动子相互作用并刺激VSMC增殖的AP 1转录因子c-fos的表达在老年VSMC中也增加。与此一致的概念，电泳迁移率变动分析表明，在老VSMCs.Conclusions的AP 1 DNA结合活性的增加：这些研究表明，年龄相关的增加c-fos活性有助于增强细胞周期蛋白A的表达和VSMC增殖在老年动物。这些机制可能有助于老年人动脉粥样硬化的患病率和严重程度较高。
Objective:Aging can be defined as a progressive deterioration of biological functions after the organism has attained its maximal reproductive competence, which is usually associated with a decrease in proliferative ability in most cell types. However, in certain pathological situations such as atherosclerosis and restenosis, aging has been shown to be associated with a higher level of vascular smooth muscle cell (VSMC) proliferation and neointimal lesion formation after angioplasty. In the present study, we investigated potential mechanisms involved in the age-dependent increase in VSMC proliferation.Methods and results:Primary cultures of VSMCs were isolated from young (6–8-month-old) and old (4–5-year-old) New Zealand rabbits. Results from cell counting assays and FACS analysis were consistent with a shortening of the cell cycle in old VSMCs. Western blot analysis in serum stimulated cells showed a significant increase in the level of cyclin A and cyclin-dependent kinase 2 proteins in the old vs. young VSMCs. In marked contrast, expression of cyclin E in VSMCs was not influenced by aging. Transient transfection assays showed an age-dependent increase in transcription from the human cyclin A promoter. Parallel studies demonstrated that the expression of the AP1 transcription factor c-fos, which interacts with the cyclin A promoter and stimulates VSMC proliferation, was also increased in old VSMCs. Consistent with this notion, electrophoretic mobility shift assays demonstrated an increase in AP1 DNA-binding activity in old VSMCs.Conclusions:These studies suggest that age-associated increase in c-fos activity contributes to augmented cyclin A expression and VSMC proliferation in old animals. These mechanisms might contribute to the higher prevalence and severity of atherosclerosis in the elderly.