组蛋白去乙酰化酶抑制剂抗血管新生机制的体内研究

摘要

目的 探讨组蛋白去乙酰化酶(HDAC)抑制剂对白血病细胞移植瘤血管新生的影响及其机制.方法 12只裸鼠均分为对照组和丙戊酸钠(VPA)用药组.建立Kasumi-1细胞裸鼠移植瘤模型,应用HDAC抑制剂VPA体内用药.RT-PCR和免疫组化检测血管内皮生长因子(VEGF)及其受体(VEGFR) mRNA或蛋白的表达；染色质免疫共沉淀法检测VEGF基因启动子区域染色质内组蛋白H3乙酰化程度的变化.结果 与对照组比较,VPA用药组VEGF及VEGFR2 mRNA和蛋白表达水平明显减少,启动子区域染色质内组蛋白H3的乙酰化程度明显升高.结论 VPA作为HDAC抑制剂,通过提高组蛋白的乙酰化程度,进而抑制血管新生相关因子及受体的表达,阻碍白血病的血管新生.%Objective To study the effect of histone deacetylase(HDAC) inhibitor on the leukemia xenograft tumor angiogenesis and its mechanisms.Methods The Kasumi-1 cell xenograft model was established in 12 nude mice,which were equally assigned into two groups of VPA [treated with HDAC inhibitor sodium valproate (VPA)] and C (control).The expressions of vascular endothelial growth factor(VEGF) and VEGF receptor 2 (VEGFR2) protein and mRNA were detected by immunohistochemistry and RT PCR.Chromatin immunoprecipitation was employed to measure the acetylation level of VEGF promotor combined H3 histone affected by VPA.Results Compared with group C,the expressions of VEGF and VEGFR2 protein and mRNA were decreased and the acetylation level of promotor combined H3 histone was increased in group VPA.Conclusion VPA as HDAC inhibitor attenuates the progression of leukemia by enhancing the acetylation and suppressing the expressions of VEGF and its receptors related to angiogenesis in leukemia.