Yang Z Y, Simari R D, Perkins N D, San H, Gordon D, Nabel G J, Nabel E G
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7905-10. doi: 10.1073/pnas.93.15.7905.
Arterial injury induces a series of proliferative, vasoactive, and inflammatory responses that lead to vascular proliferative diseases, including atherosclerosis and restenosis. Although several factors have been defined which stimulate this process in vivo, the role of specific cellular gene products in limiting this response is not well understood. The p21 cyclin-dependent kinase inhibitor affects cell cycle progression, senescence, and differentiation in transformed cells, but its expression in injured blood vessels has not been investigated. In this study, we report that p21 protein is induced in porcine arteries following balloon catheter injury and suggest that p21 is likely to play a role in limiting arterial cell proliferation in vivo. Vascular endothelial and smooth muscle cell growth was arrested through the ability of p21 to inhibit progression through the G1 phase of the cell cycle. Following injury to porcine arteries, p21 gene product was detected in the neointima and correlated inversely with the location and kinetics of intimal cell proliferation. Direct gene transfer of p21 using an adenoviral vector into balloon injured porcine arteries inhibited the development of intimal hyperplasia. Taken together, these findings suggest that p21, and possibly related cyclin-dependent kinase inhibitors, may normally regulate cellular proliferation following arterial injury, and strategies to increase its expression may prove therapeutically beneficial in vascular diseases.
动脉损伤会引发一系列增殖、血管活性和炎症反应，进而导致血管增殖性疾病，包括动脉粥样硬化和再狭窄。尽管已经确定了一些在体内刺激这一过程的因素，但特定细胞基因产物在限制这种反应中的作用尚未得到充分了解。p21细胞周期蛋白依赖性激酶抑制剂会影响转化细胞的细胞周期进程、衰老和分化，但其在受损血管中的表达尚未得到研究。在本研究中，我们报告称，在猪动脉经球囊导管损伤后会诱导p21蛋白表达，并表明p21可能在体内限制动脉细胞增殖中发挥作用。通过p21抑制细胞周期G1期进程的能力，血管内皮细胞和平滑肌细胞的生长被阻滞。在猪动脉损伤后，在新生内膜中检测到p21基因产物，且其与内膜细胞增殖的位置和动力学呈负相关。使用腺病毒载体将p21直接基因转移到经球囊损伤的猪动脉中，可抑制内膜增生的发展。综上所述，这些发现表明p21以及可能相关的细胞周期蛋白依赖性激酶抑制剂，可能正常调节动脉损伤后的细胞增殖，并且增加其表达的策略可能在血管疾病治疗中被证明是有益的。
