转录辅激活因子p300参与血管紧张素Ⅱ诱导的心房肌细胞I_(kur)离子通道重构的调控  

Transcriptional co-activator p300 involves in the increase of Ikur induced by angiotensinⅡin atrial myocytes

作　　者：曾珑 余声欢 肖海茵 肖菲菲 朱蕊 邓春玉[2] 杨慧[2] 邝素娟[2] 饶芳 魏薇[1,2] ZENG Long;YU Sheng-huan;XIAO Hai-yin;XIAO Fei-fei;ZHU Rui;DENG Chun-yu;YANG Hui;KUANG Su-juan;RAO Fang;WEI Wei(School of Medicine,South China University of Technology,Guangzhou 510006,China)

机构地区：[1]华南理工大学医学院,广东广州510006 [2]广东省医学科学院广东省人民医院

出　　处：《中国介入心脏病学杂志》2022年第10期783-790,共8页Chinese Journal of Interventional Cardiology

基　　金：国家自然科学基金青年科学基金项目(81900301);广州市科技计划项目(201904010451);广州市科技计划项目(201804010059)。

摘　　要：目的探讨转录辅激活因子p300是否参与调控心房肌细胞Kv1.5蛋白的表达。方法以Western Blot检测细胞和C57BL/6小鼠心房组织p300蛋白、钾离子通道蛋白Kv1.5的表达。HL-1细胞在血管紧张素Ⅱ(AngⅡ)刺激的基础上使用p300抑制剂姜黄素或p300 siRNA干预,观察p300对Kv1.5蛋白表达以及超速延迟整流钾电流(I_(kur))的作用。全细胞膜片钳技术检测各组细胞的I_(kur)和动作电位时程(APD)。快速起搏心房观察小鼠心房颤动(房颤)的可诱发性。结果动物实验显示,与对照组相比,AngⅡ处理组小鼠有着明显更高的房颤诱发率(P<0.01),心耳组织p300以及Kv1.5蛋白表达明显升高(均P<0.05),而姜黄素干预后可以明显减少小鼠的房颤诱发率(P<0.01),并使p300和Kv1.5蛋白表达减少(P<0.05)。细胞实验显示,和对照组相比,AngⅡ处理组HL-1细胞p300以及Kv1.5蛋白表达明显升高(P<0.05),I_(kur)电流密度上升,APD缩短。在分别用p300抑制剂姜黄素和p300 siRNA干预后表现为p300和Kv1.5蛋白表达减少(P<0.05),I_(kur)电流密度下降,APD延长。结论AngⅡ可通过p300引起心房肌细胞Kv1.5蛋白表达上升,I_(kur)电流密度上升,引起心房肌细胞电重构。Objective To investigate whether transcriptional co-activator p300 participates in the regulation of Kv1.5 expression in atrial myocytes.Methods Western Blot was used to determine the expression levels of Kv1.5 and p300 in the cell and C57BL/6 mice atrial tissues.Based on the treatment of angiotensinⅡ(AngⅡ),curcumin,an inhibitor of p300,as well as p300 siRNA was used to investigate its functional effect on expression of Kv1.5 and current density of ultra-rapid delayed rectifier K(+)current(I_(kur)).Whole-cell-patch-clamp was to record the current density of atrial-specific I_(kur)and action potential duration(APD).The susceptibility of atrial fibrillation was detected by electrophysiological examination.Results The incidence of AF was significantly higher in AngⅡ-treated mice(P<0.01)and could be suppressed by curcumin(P<0.01).In the LA tissues from AngⅡ-treated mice,p300 and Kv1.5 protein expression increased(both P<0.05),and these changes could be reversed by curcumin(P<0.05).Expression of p300 and Kv1.5 was significantly increased in angiotensinⅡ-treated HL-1 cell compared with control group(P<0.05).The results of whole-cell-patch clamp showed that angiotensinⅡ-treated HL-1 had higher I_(kur)current density and shorter APD compared with control group(P<0.01).However,p300 inhibitor curcumin could restored I_(kur),APD and expression of Kv1.5 induced by angiotensinⅡ(P<0.05).The same results were also found when p300 was gene-silenced with siRNA.Conclusions AngiotensinⅡinduces Kv1.5 upregulation via co-activator p300 in atrial myocytes.Inhibition of p300 may be beneficial for atrial fibrillation treatment by abrogate the upregulation of Kv1.5 induced by angiotensinⅡ.

关 键 词：P300 血管紧张素Ⅱ 心房颤动 Kv1.5蛋白 心房肌细胞 

分 类 号：R541.7[医药卫生—心血管疾病]