肥厚型心肌病中哺乳动物Ste20样激酶1的表达及其作用机制研究  

The expression and mechanism of action of mammalian Ste20‑like kinase 1 in hypertrophic cardiomyopathy

作　　者：刘冬[1] 党海明[1] 宋跃[1] 曹剑[1] 吴立松[1] 黄琦[1] 董然[1] Liu Dong;Dang Haiming;Song Yue;Cao Jian;Wu Lisong;Huang Qi;Dong Ran(Department of Cardiac Surgery,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院心脏外科,北京100029

出　　处：《中华心力衰竭和心肌病杂志（中英文）》2021年第3期173-178,共6页Chinese Journal of Heart Failure and Cardiomyopathy

摘　　要：目的探讨哺乳动物Ste20样激酶1(MST1)基因表达与肥厚型心肌病(HCM)心肌肥厚发生发展的相关性并确定相关的信号传导通路。方法收集20例HCM患者肥厚的室间隔心肌组织及4例健康对照者的正常心肌组织,首先从临床标本(HCM患者及正常对照组)、动物模型(MST1基因敲除小鼠模型及经主动脉弓缩窄TAC小鼠模型)及体外细胞培养模型,证实MST1基因表达与HCM的心肌肥厚有关;然后,通过细胞(H9C2)水平、动物模型及临床标本水平验证MST1信号通路(包括MST1、YAP2、Survivin及AKT)在HCM发生发展中的作用。结果(1)与正常心肌组织比较,MST1基因在HCM患者组织中蛋白表达及RNA转录水平均明显下降,而且,HCM患者中MST1基因蛋白表达水平与超声心动图检查的室间隔厚度呈负相关。(2)MST1基因敲除小鼠的心室壁厚度及心脏体重比均高于对照组(MST1基因野生型)小鼠;TAC组小鼠的心室壁厚度及心脏体重比也均高于假手术组;而MST1基因敲除并行TAC小鼠的心室壁厚度及心脏体重比明显高于对照组。(3)体外细胞培养结果显示,MST1基因低表达时可以促进心肌细胞肥大。(4)通过细胞(H9C2)水平、动物模型及临床标本水平进行验证发现,MST1基因表达下调,通过下游相关基因(YAP2及Survivin)表达上调及相关特异性基因(AKT)的活性表达,可以促进心肌细胞增生,从而导致心肌肥厚的形成。结论MST1基因的表达降低与HCM的发生相关,其表达降低时可通过调节下游基因YAP2及Survivin的表达上调,进而影响AKT的活性,从而促进心肌细胞增生,导致心肌肥厚的形成以及HCM的发生。Objective To investigate the relationship between the expression of mammalian Ste20-like kinase 1(MST1)and cardiac hypertrophy in hypertrophic cardiomyopathy(HCM)and to determine the associated signaling pathway.Methods Hypertrophied inter-ventricular septal tissues from 20 patients with HCM and normal myocardial tissues from 4 healthy control group were collected.Firstly,clinical specimens including HCM patients and normal control group,animal models including MST1 gene knockout(KO)mouse model and transverse aortic constriction(TAC)mouse model,and in vitro cell culture models were used to confirm the correlation between MST1 gene expression and cardiac hypertrophy.Then,the role of MST1 signaling pathway including MST1,YAP2,Survivin and AKT in the pathogenesis and development of HCM was verified by cell(H9C2)level,animal model level and clinical specimen level.Results(1)Compared with normal myocardium,the levels of protein expression and RNA transcription of MST1 gene were significantly decreased in patients with HCM.Moreover,the level of protein expression of MST1 gene was negatively correlated with inter-ventricular septal thickness detected by echocardiograpy in patients with HCM.(2)The ventricular wall thickness and heart weight ratio of MST1 gene KO mice were higher than those of control mice(MST1 gene wild-type).The ventricular wall thickness and heart weight ratio in TAC group were also higher than those in sham group.Furthermore,the ventricular wall thickness and heart weight ratio of mice with MST1 gene KO and TAC were significantly higher than those of control group.(3)In vitro cell culture results showed that lower expression of MST1 gene could promote cardiac hypertrophy.(4)In addition,down-regulation of MST1 gene expression can lead to up-regulation of downstream related genes(YAP2 and Survivin)and active expression of related specific gene(AKT)and subsequently to promote cardiac hypertrophy,which is verified by cell(H9C2)level,animal model and clinical specimen level.Conclusions The abnormal express

关 键 词：心肌病 肥厚型 哺乳动物Ste20样激酶1 信号通路 基因学 

分 类 号：R542.2[医药卫生—心血管疾病]