单硝酸异山梨酯上调外泌体-microRNA378表达减轻机械牵张诱导的心力衰竭  

Isosorbide mononitrate inhibits mechanical stress-induced heart failure through upregulating expression of exosomal-microRNA378

作　　者：张卫君 刘琳琳 林利[1] ZHANG Wei-jun;LIU Lin-lin;LIN Li(Dept.of Cardiology,East Hospital,Tongji University,Shanghai 200120,China)

机构地区：[1]同济大学附属东方医院心血管内科,上海200120

出　　处：《同济大学学报（医学版）》2018年第3期24-29,共6页Journal of Tongji University(Medical Science)

基　　金：国家自然科学基金(81570237);中国医师协会项目(DFCMDA201259)

摘　　要：目的探讨单硝酸异山梨酯(isosorbide mononitrate,ISMN)对机械牵张诱导的心力衰竭的作用及与外泌体-microRNA378的关系。方法对C57BL/6小鼠施行升主动脉缩窄术(transverse aortic constriction,TAC)4周后建立在体压力超负荷诱导心力衰竭模型,对培养的心肌细胞机械牵张48 h后构成离体压力超负荷诱导心力衰竭模型。在体实验分为3组:对照组、升主动脉缩窄组(TAC组)、升主动脉缩窄+单硝酸异山梨酯组(TAC+ISMN组)。离体实验分为5组:对照组、牵张组、牵张+microRNA378类似物组、牵张+ISMN组、牵张+ISMN+microRNA378抑制剂组。4周后进行心超检查,测定心质量/体质量、心肌细胞形态、血浆NT-pro BNP,外泌体-microRNA378表达。机械牵张48 h后,收集细胞提取RNA,RT-q PCR检测ANP、SAA的表达。结果 TAC+ISMN组较TAC组左心室舒张末期内径、左心室舒张末期前壁厚度、心质量/体质量、NT-pro BNP水平明显下降(P<0.01、P<0.05、P<0.01、P<0.01),短轴缩短率明显升高(P<0.05)。RT-q PCR显示TAC+ISMN组较TAC组外泌体-microRNA378表达明显上调(P<0.05)。牵张+ISMN组、牵张+microRNA378类似物组较牵张组ANP、SAA表达下降(P<0.05),牵张+ISMN+microRNA378抑制剂组较牵张组ANP、SAA表达下降不明显(P>0.05)。结论ISMN通过上调外泌体-microRNA378的表达减轻机械牵张诱导的心力衰竭。Objective To investigate the effects of isosorbide mononitrate（ ISMN） on mechanical stress-induced heart failure and its relation to exosomal-microRNA378（ miRNA378）. Methods The pressure overload heart failure model in vivo and in vitro were induced by transverse aortic constriction（ TAC） in C57 BL/6 mice for 4 weeks or by mechanical stretch on cultured cardiomyocytes for 48 h,respectively. Fifteen C57 BL/6 male mice were divided into control group,ascending aortic constriction group（ TAC group） and ascending aortic constriction ＋ ISMN group（ TAC ＋ ISMN group） in vivo experiment. The cultured cardiomyocytes were divided into 5 groups： control group,stretch group,stretch＋miRNA378 mimic group,stretch＋ISMN group and stretch＋ISMN＋miRNA378 inhibitor group.The echocardiography,heart weight/body weight ratio（ HW/BW）,the morphology of cardiomyocyte,plasma NT-proBNP and the expression of exosomal-microRNA378 were examined for in vivo model.The cardiomyocytes were collected and the mRNA expression of atrial natriuretic peptide（ ANP） and skeletal-α-actin（ SAA） was detected with RT-qPCR for in vitro model. Results In in vivo experiments,the LVIDd,LVAWd,HW/BW and plasma NT-proBNP levels in TAC ＋ISMN group were significantly lower than those in TAC group（ P〈0.05）,FS in TAC＋ISMN group was significantly higher than that in TAC group（ P〈0. 05）. RT-qPCR shows that the expression of exosomalmicroRNA378 was significantly upregulated in TAC ＋ ISMN group compared with TAC group（ P〈0. 05）. In in vitro experiments,the expressions of ANP and SAA in cardiomyocytes were significantly decreased in stretch＋ISMN group and stretch＋microRNA378 mimic group compared with stretch group（ P〈0. 05）,however,there were no significant differences between stretch ＋ ISMN ＋microRNA378 inhibitor group and stretch group（ P〈0.05）. Conclusion Isosorbide mononitrate inhibits mechanical stress-induced heart failure through upregulation of the exosomal-microRNA378 expressio

关 键 词：单硝酸异山梨酯 外泌体-microRNA378 机械牵张 心力衰竭 

分 类 号：R541.6[医药卫生—心血管疾病]