Zettler Marjorie E, Merchant Michele A, Pierce Grant N
Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, and Department of Physiology, Faculties of Medicine and Pharmacy, University of Manitoba, Winnipeg, Manitoba.
Exp Clin Cardiol. 2010 Winter;15(4):e139-44.
Cell proliferation within a primary atherosclerotic plaque is controversial. Identifying changes in cell cycle protein expression and the activities of their related kinases would provide valuable evidence of mitotic activity in the atherosclerotic lesion. Oxidized low-density lipoprotein has been shown to induce a significant increase in the total number of rabbit vascular smooth muscle cells in culture. In the present study, whole aortic cell extracts were harvested from rabbits fed a cholesterol-supplemented diet for eight weeks to induce modest plaque development, or 16 weeks to induce later, more severe plaque progression. Expression levels of cyclin A, cyclin-dependent kinase 4 (Cdk 4) and proliferating cell nuclear antigen were measured, as well as the activities of Cdk 4, Cdk 2 and Cdk 1. At both time points, the expression levels of cyclin A, Cdk 4 and proliferating cell nuclear antigen were significantly elevated. The activity of all three Cdks was also increased. There were no significant differences between moderate and more severe atherosclerosis. Surprisingly, tissues that neighboured the plaques, but did not show visible plaque formation on the vessel surface, also had significantly elevated cyclin A expression levels, but not as high as in the plaque areas. In conclusion, the primary atherosclerotic plaque exhibited elevated mitotic activity as shown by increased expression levels and activities of several cell cycle proteins. Expression levels were similar during moderate and severe atherosclerosis, and were even detected in nonatherosclerotic vascular tissue bordering the plaque.
原发性动脉粥样硬化斑块内的细胞增殖存在争议。确定细胞周期蛋白表达及其相关激酶活性的变化将为动脉粥样硬化病变中的有丝分裂活性提供有价值的证据。氧化型低密度脂蛋白已被证明可使培养的兔血管平滑肌细胞总数显著增加。在本研究中，从喂食含胆固醇饮食8周以诱导适度斑块形成的兔子或16周以诱导后期更严重斑块进展的兔子中采集全主动脉细胞提取物。测量细胞周期蛋白A、细胞周期蛋白依赖性激酶4（Cdk 4）和增殖细胞核抗原的表达水平，以及Cdk 4、Cdk 2和Cdk 1的活性。在两个时间点，细胞周期蛋白A、Cdk 4和增殖细胞核抗原的表达水平均显著升高。所有三种Cdk的活性也增加。中度和重度动脉粥样硬化之间没有显著差异。令人惊讶的是，与斑块相邻但在血管表面未显示可见斑块形成的组织，其细胞周期蛋白A表达水平也显著升高，但不如斑块区域高。总之，原发性动脉粥样硬化斑块表现出有丝分裂活性升高，表现为几种细胞周期蛋白的表达水平和活性增加。在中度和重度动脉粥样硬化期间表达水平相似，甚至在与斑块相邻的非动脉粥样硬化血管组织中也能检测到。
