HMGB-1抑制剂甘草酸对急性心肌梗死大鼠炎性损伤及JAK/STAT、Wnt3a通路的影响

Effects of glycyrrhizic acid,a HMGB-1 inhibitor,on inflammatory injury and JAK/STAT,Wnt3a pathways in rats with acute myocardial infarction

目的探究高迁移率族蛋白(HMGB)-1抑制剂甘草酸对急性心肌梗死大鼠心肌组织的保护作用及可能的作用机制。方法建立心肌梗死模型大鼠,分为模型组、甘草酸低、中、高剂量组、阳性对照组(卡托普利),另设假手术组,每组均10只大鼠。超声检测大鼠心室功能变化情况;氯化三苯基四氮唑(TTC)染色观察大鼠心肌组织梗死情况;苏木素-伊红(HE)染色观察心肌组织形态学变化情况;酶联免疫吸附试验检测血清中肿瘤坏死因子(TNF)-α、单核细胞趋化蛋白(MCP)-1水平;免疫印迹法检测心肌组织中酪氨酸激酶/信号转导与转录激活子(JAK/STAT)、Wnt3a通路蛋白表达情况。结果与假手术组相比,模型组左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、心肌梗死面积比、血清TNF-α、MCP-1水平、心肌组织中HMGB-1、Wnt3a、β-catenin蛋白表达明显升高(P<0.05),左心室射血分数(LVEF)、左心室短轴缩短率(FS)、JAK2蛋白、STAT3蛋白磷酸化水平明显降低(P<0.05)。与模型组相比,甘草酸各剂量组及卡托普利组LVEDD、LVESD、心肌梗死面积比、TNF-α、MCP-1水平、HMGB-1、Wnt3a、β-catenin蛋白表达明显降低(P<0.05),LVEF、FS、JAK2蛋白、STAT3蛋白磷酸化水平明显升高(P<0.05)。随着甘草酸剂量的增加,甘草酸各剂量组LVEDD、LVESD、心肌梗死面积比、TNF-α、MCP-1水平、HMGB-1、Wnt3a、β-catenin蛋白表达逐渐降低,LVEF、FS、JAK2蛋白、STAT3蛋白磷酸化水平逐渐升高,且呈剂量依赖性(P<0.05)。甘草酸高剂量组与卡托普利组比较,差异无统计学意义(P>0.05)。结论HMGB-1抑制剂甘草酸能够对心肌梗死大鼠心肌损伤发挥保护作用,这可能通过激活JAK/STAT通路,抑制Wnt3a通路从而缓解心肌梗死造成的的心肌炎症损伤。

Objective To investigate the protective effect of glycyrrhizic acid,a high mobility group protein(HMGB)-1 inhibitor,on myocardial tissue of rats with acute myocardial infarction(AMI)and its possible mechanism.Methods The AMI model rats were established and divided into model group(AMI),glycyrrhizic acid low dose group,middle dose group and high dose group,positive drug control group(captopril),and sham group was set up,with 10 rats in each group.The changes of ventricular function were detected by ultrasound;TTC staining was used to observe myocardial infarction;HE staining was used to observe the changes of myocardial morphology;the levels of TNF-αand MCP-1 in serum were detected by ELISA;and Western blot was used to detect the expressions of JAK/STAT and Wnt3 a pathway proteins.Results Compared with sham group,the left ventricular end diastolic diameter(LVEDD),left ventricular end systolic diameter(LVESD),myocardial infarct area ratio,the levels of serum TNF-αand MCP-1,the protein expressions of HMGB-1,Wnt3 a andβ-catenin in myocardial tissue were significantly increased(P<0.05),while the left ventricular ejection fraction(LVEF),left heart fractional shortening(FS),the levels of JAK2 and STAT3 proteins phosphorylation significantly decreased in model group(P<0.05).Compared with model group,the LVEDD,LVESD,myocardial infarct area ratio,the levels of TNF-αand MCP-1,the protein expressions of HMGB-1,Wnt3 a andβ-catenin significantly decreased(P<0.05),while the LVEF,FS,the levels of JAK2 and STAT3 proteins phosphorylation significantly increased in glycyrrhizic acid groups and captopril group(P<0.05).With the increasing of dose of glycyrrhizic acid,the LVEDD,LVESD,myocardial infarct area ratio,the levels of TNF-αand MCP-1,the protein expressions of HMGB-1,Wnt3 a andβ-catenin decreased gradually,while the LVEF,FS,the levels of JAK2 and STAT3 proteins phosphorylation increased gradually in dose-dependent manner.There were no significant differences in above indexes between high dose glycyrrhizic acid group and captopril group(P>0.05).Conclusions Glycyrrhizic acid,an inhibitor of HMGB-1,could play a protective role in myocardial injury of AMI rats,it might alleviate the myocarditis injury caused by AMI by activating JAK/STAT pathway and inhibiting Wnt3 a pathway.