Wei G L, Krasinski K, Kearney M, Isner J M, Walsh K, Andrés V
Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass. 02135, USA.
Circ Res. 1997 Mar;80(3):418-26.
Intimal hyperplasia following angioplasty results in part from the migration and proliferation of vascular smooth muscle cells (VSMCs). However, the cell cycle regulatory networks underlying injury-induced VSMC proliferation are largely unknown. In the present study, we examined the kinetics of expression and activity of cell cycle regulatory factors after angioplasty in rat and human arteries. Cell lysates were prepared from uninjured rat carotid arteries and at different time points after balloon denudation. Marked induction of the proliferating cell nuclear antigen (PCNA), the G1/S cyclin-dependent kinase (cdk2), and its regulatory subunits (cyclin E and cyclin A) occurred between 1 and 2 days after angioplasty, was sustained up to 10 days after injury, and then declined. Induction of these factors correlated with increased cdk2-, cyclin E-, and cyclin A-dependent kinase activity, indicating the assembly of functional cdk2/cyclin E and cdk2/cyclin A holoenzymes in the injured arterial wall. Immunohistochemical analysis revealed early expression of cdk2, cyclin E, and PCNA within the media of injured carotid arteries. At later time points, expression of these markers declined to basal levels in the media but was detected within the intimal lesion. Thus, VSMC proliferation after angioplasty in the rat carotid artery is associated with a temporally and spatially coordinated expression of cdk2, cyclins E and A, and PCNA. Analysis of human arteries also revealed expression of these factors in VSMCs within restenotic lesions. Thus, cdk2 and its regulatory cyclins may be suitable targets to limit human restenosis.
血管成形术后的内膜增生部分源于血管平滑肌细胞（VSMC）的迁移和增殖。然而，损伤诱导的VSMC增殖背后的细胞周期调控网络在很大程度上尚不清楚。在本研究中，我们检测了大鼠和人类动脉血管成形术后细胞周期调控因子的表达动力学和活性。从未损伤的大鼠颈动脉以及球囊剥脱术后不同时间点制备细胞裂解物。增殖细胞核抗原（PCNA）、G1/S细胞周期蛋白依赖性激酶（cdk2）及其调节亚基（细胞周期蛋白E和细胞周期蛋白A）在血管成形术后1至2天出现明显诱导，在损伤后持续至10天，然后下降。这些因子的诱导与cdk2、细胞周期蛋白E和细胞周期蛋白A依赖性激酶活性增加相关，表明在损伤的动脉壁中功能性cdk2/细胞周期蛋白E和cdk2/细胞周期蛋白A全酶的组装。免疫组织化学分析显示，cdk2、细胞周期蛋白E和PCNA在损伤的颈动脉中膜内早期表达。在后期时间点，这些标志物的表达在中膜下降至基础水平，但在内膜病变中被检测到。因此，大鼠颈动脉血管成形术后VSMC增殖与cdk2、细胞周期蛋白E和A以及PCNA在时间和空间上的协调表达相关。对人类动脉的分析也显示这些因子在再狭窄病变内的VSMC中表达。因此，cdk2及其调节性细胞周期蛋白可能是限制人类再狭窄的合适靶点。
