骨成型蛋白-4参与糖尿病心肌病“高糖记忆”现象的机制  

Novel mechanism of bone morphogenetic protein-4 involvement in “hyperglycemic memory” in diabetic cardiomyopathy

作　　者：王玉春 王宇婷[3] 王娟娟 孙英姿 王子豪 葛鹏玲 刘吉成[1] Wang Yuchun;Wang Yuting;Wang Juanjuan;Sun Yingzi;Wang Zihao;Ge Pengling;Liu Jicheng(Post-Doctoral Research Center,Qiqihar Institute of Medical Sciences,Qiqihar,Heilongjiang 161006,China;Mobile Postdoctoral Center,Heilongjiang University of Chinese Medicine,Harbin,Heilongjiang 150040,China;School of Pharmacy,Qiqihar Medical University,Qiqihar,Heilongjiang 161006,China)

机构地区：[1]齐齐哈尔医药科学研究所博士后工作站,黑龙江齐齐哈尔161006 [2]黑龙江中医药大学博士后流动站,黑龙江哈尔滨150040 [3]齐齐哈尔医学院药学院,黑龙江齐齐哈尔161006

出　　处：《齐齐哈尔医学院学报》2024年第4期301-305,共5页Journal of Qiqihar Medical University

基　　金：齐齐哈尔医学科学院临床科研基金项目(QMSI2021L-01);黑龙江省自然科学基金(H2016099)。

摘　　要：目的 研究骨成型蛋白-4(BMP4)在糖尿病心肌病(DCM)“高糖记忆”中的作用。方法 体外实验:原代培养C57BL/6小鼠乳鼠心肌细胞,随机分为正常浓度葡萄糖组(Normal glucose,NG)、高浓度葡萄糖组(High glucose,HG)、“高糖记忆”组(HGNG),分别采用NG(5.6 mM)、HG(33 mM)、HG培养4 d+NG培养4 d,每组均培养8 d。培养结束后采用Western Blotting(WB)法检测凋亡蛋白Caspase-3及BMP4在DCM心肌细胞中的表达情况。以BMPs受体抑制剂DMH1作用于DCM“高糖记忆”模型细胞,观察Caspase-3及BMP4表达变化。体内实验:注射链脲佐菌素(50 mg/kg)连续5 d建立糖尿病C57BL/6小鼠模型,每日给予二甲双胍(Metformin,MET,320 mg/kg)灌胃治疗,连续给药8周,血糖仪检测血糖、WB法检测caspase-3及BMP4在小鼠心脏组织中表达情况。结果 在HG组中,HG可明显诱导心肌细胞BMP4蛋白表达,与NG组比较差异显著(P<0.01);DCM“高糖记忆”模型(HGNG组)心肌细胞BMP4蛋白表达显著升高,与NG组比较差异显著(P<0.01),与HG组比较无统计学差异(P>0.05)。DMH1可明显抑制DCM“高糖记忆”模型细胞中BMP4及Caspase-3蛋白表达(P<0.01)。MET可降低糖尿病小鼠血糖及心体比指数,抑制Caspase-3蛋白表达(P<0.01),但并不抑制BMP4蛋白表达。结论 BMP4是产生DCM“高糖记忆”现象的机制之一,BMPs受体抑制剂DMH1改善DCM“高糖记忆”引起的心肌细胞损伤。Objective To explore the role of bone morphogenetic protein-4(BMP4) in "hyperglycemic memory" in diabetic cardiomyopathy(DCM).Methods Primary cultured cardiomyocytes of C57BL/6 neonatal mouse were randomly divided into the normal glucose group(NG),the high glucose group(HG) and the hyperglycemic memory group(HGNG).The cells were cultured with normal concentration of glucose(NG,5.6 mM),high concentration of glucose(HG,33 mM) and 4 days of HG glucose followed by 4 days of normal concentration of glucose(NG,5.6 mM) medium,respectively,each group was cultured for 8 days.Western Blotting(WB) method was used to detect the expressions of caspase3 and BMP4 in DCM cardiomyocytes.DMH1,a BMPs receptor inhibitor was applied to “hyperglycemic memory” model in DCM to observe the expression changes of caspase3 and BMP4.In vivo experiment:A C57BL/6 mouse model of diabetes mellitus was established by injection of streptozotocin(50 mg/kg) for 5 consecutive days,and Metformin(MET,320mg/kg) was given daily by gavage for 8 weeks.A glucose meter was used to measure blood sugar.The expression of caspase3 and BMP4 in mouse heart tissue was detected by WB method.Results HG could significantly induce the expression of BMP4 protein in cardiomyocytes compared with NG group(P<0.01).The expression of BMP4 protein was significantly higher in “hyperglycemic memory” cardiomyocytes in DCM than that in NG group(P<0.01),and there was no significant difference compared with HG group(P>0.05).DMH1 inhibited the expression of BMP4 and casepase3 proteins in “hyperglycemic memory” cardiomyocytes in DCM(P<0.01).MET decreased blood glucose and heart-body ratio index in diabetic mice,and inhibited the expression of casepase3 protein(P<0.01),but did not inhibit BMP4 protein expression.Conclusions BMP4 is involved in the “hyperglycemic memory” in DCM.BMPs receptor inhibitor DMH1 can improve the damage of cardiomyocytes caused by“hyperglycemic memory”in DCM.

关 键 词：糖尿病心肌病 骨成型蛋白-4 “高糖记忆” 二甲双胍 

分 类 号：R542.2[医药卫生—心血管疾病]