Sanz-González Silvia M, Melero-Fernández de Mera Raquel, Malek Nisar P, Andrés Vicente
Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Valencia, Spain.
J Cell Biochem. 2006 Mar 1;97(4):735-43. doi: 10.1002/jcb.20680.
Excessive cellular proliferation is thought to contribute to neointimal lesion development during atherosclerosis and restenosis after angioplasty. Inhibition of cyclin-dependent kinase (CDK) activity by p27 inhibits mammalian cell growth. Mounting evidence indicates that p27 negatively regulates neointimal thickening in animal models of restenosis and atherosclerosis, and its expression in human neointimal lesions is consistent with such a protective role. Cell cycle progression is facilitated by cyclinE/CDK2-dependent phosphorylation of p27 on threonine 187 (T187) during late G1. The purpose of this study was to assess whether this phosphorylation event plays a role during atherosclerosis. To this end, we generated apolipoprotein E-null mice with both p27 alleles replaced by a mutated form non-phosphorylatable at T187 (apoE-/-p27T187A mice) and investigated the kinetics of atheroma development in these animals compared to apoE-/- controls with an intact p27 gene. Fat feeding resulted in comparable level of hypercholesterolemia in both groups of mice. Surprisingly, aortic p27 expression was not increased in fat-fed apoE-/-p27T187A mice compared with apoE-/- controls. Moreover, atheroma size, lesion cellularity, proliferation, and apoptotic rates were undistinguishable in both groups of fat-fed mice. Thus, in contrast to previous studies that highlight the importance of p27 phosphorylation at T187 on the control of p27 expression and function in different tissues and pathophysiological scenarios, our findings demonstrate that this phosphorylation event is not implicated in the control of aortic p27 expression and atheroma progression in hypercholesterolemic mice.
细胞过度增殖被认为在动脉粥样硬化和血管成形术后再狭窄过程中会导致新生内膜病变的发展。p27对细胞周期蛋白依赖性激酶（CDK）活性的抑制作用会抑制哺乳动物细胞的生长。越来越多的证据表明，p27在再狭窄和动脉粥样硬化动物模型中对新生内膜增厚起负向调节作用，并且其在人类新生内膜病变中的表达与这种保护作用一致。在G1晚期，细胞周期蛋白E/CDK2依赖性的p27苏氨酸187（T187）位点磷酸化促进细胞周期进程。本研究的目的是评估该磷酸化事件在动脉粥样硬化过程中是否发挥作用。为此，我们构建了载脂蛋白E基因缺失且两个p27等位基因均被T187位点不可磷酸化的突变形式所取代的小鼠（apoE-/-p27T187A小鼠），并研究了与具有完整p27基因的apoE-/-对照小鼠相比，这些动物动脉粥样硬化发展的动力学情况。两组小鼠喂食高脂饲料后均出现了相当程度的高胆固醇血症。令人惊讶的是，与apoE-/-对照小鼠相比，喂食高脂饲料的apoE-/-p27T187A小鼠主动脉p27表达并未增加。此外，两组喂食高脂饲料的小鼠在动脉粥样硬化斑块大小、病变细胞构成、增殖和凋亡率方面并无差异。因此，与之前强调T187位点p27磷酸化在不同组织和病理生理情况下对p27表达和功能控制重要性的研究相反，我们的研究结果表明，该磷酸化事件与高胆固醇血症小鼠主动脉p27表达及动脉粥样硬化进展的控制无关。
