Single perivascular delivery of mitomycin C stimulates p21 expression and inhibits neointima formation in rat arteries
Single perivascular delivery of mitomycin C stimulates p21 expression and inhibits neointima formation in rat arteries
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DOI：
10.1161/01.atv.0000184779.01822.9d
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发表时间：
2005-11-01
影响因子：
8.7
通讯作者：
Durante, W
中科院分区：
文献类型：
--
作者：
Granada, JF;Ensenat, D;Durante, W
目的：丝裂霉素C(MMC)是一种在肿瘤细胞中具有很强的抗增殖作用的抗生素。由于血管平滑肌细胞(VSMCs)的增殖在经皮冠状动脉介入治疗后再狭窄的发生中起重要作用，本研究观察了MMC对血管球囊损伤后VSMC增殖和新生内膜形成的影响。方法与结果：MMC(1nmol~30mMol/L)对培养的大鼠主动脉VSMC的增殖具有浓度依赖性的抑制作用。高浓度MMC(1~30mU·mol/L)诱导VSMC凋亡，表现为DNA梯状条带和caspase-3激活；低浓度MMC(1~300nmol/L)通过将细胞阻滞在细胞周期的G(2)/M期而直接抑制VSMC的生长。MMC的抗增殖作用与选择性增加细胞周期蛋白依赖性激酶抑制因子p21的表达，降低细胞周期蛋白B1-细胞周期蛋白依赖性激酶-1复合体的活性有关。大鼠颈动脉球囊损伤后即刻局部血管周围注射MMC可诱导p21表达，并显著抑制新生内膜形成。结论：MMC对动脉损伤后VSMC的增殖和新生内膜形成有明显的抑制作用。MMC在治疗和预防血管增生性疾病方面是一种潜在的新的治疗药物。
Objective-Mitomycin C (MMc) is an antibiotic that exerts a potent antiproliferative effect in tumor cells. Because the proliferation of vascular smooth muscle cells (VSMCs) plays a prominent role in the development of restenosis after percutaneous coronary interventions, the present study examined the effect of MMc on VSMC proliferation and on neointima formation after arterial balloon injury.Methods and Results-Treatment of cultured rat aortic VSMCs with MMc (1 nmol to 30 mu mol/L) inhibited VSMC proliferation in a concentration-dependent manner. Whereas high concentrations of MMc (1 to 30 mu mol/L) induced VSMC apoptosis, as reflected by DNA laddering and caspase-3 activation, lower concentrations of MMc (1 to 300 nmol/L) directly inhibited VSMC growth by arresting cells in the G(2)/M phase of the cell cycle. The antiproliferative action of MMc was associated with a selective increase in the expression of the cyclin-dependent kinase inhibitor p21, and with a decrease in cyclin B1-cyclin-dependent kinase-1 complex activity. Finally, the local perivascular delivery of MMc immediately after balloon injury of rat carotid arteries induced p21 expression and markedly attenuated neointima formation.Conclusion-These studies demonstrate that MMc exerts a potent inhibitory effect on VSMC proliferation and neointima formation after arterial injury. MMc represents a potentially new therapeutic agent in treating and preventing vasculoproliferative disease.