醛固酮受体拮抗剂螺内酯减轻肢体缺血再灌注致心肌损伤的信号传导机制

Signal Transduction Mechanism of Aldosterone Receptor Antagonist Spironolactone in Reducing Myocardial Injury Caused by Limb Ischemia-reperfusion

目的:分析醛固酮受体拮抗剂螺内酯减轻肢体缺血再灌注致心肌损伤的信号传导机制。方法:将30只健康Wistar雄性大鼠随机分为对照组(10只,正常饲养)、再灌注组(10只,建立肢体缺血再灌注大鼠模型)、螺内酯组(10只,建立模型前给予螺内酯)。检测3组大鼠心肌损伤指标、炎症反应及氧化应激反应变化。结果:对照组大鼠心肌细胞凋亡率为(5.28±1.05)%,再灌注组为(185.47±35.85)%,螺内酯组为(75.25±24.19)%,3组比较差异有统计学意义(P<0.05)。再灌注组、螺内酯组血清肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)、心肌肌钙蛋白I(cTnI)表达较对照组增加;螺内酯组血清cTnI、CK、CK-MB表达低于再灌注组(P<0.05)。再灌注组、螺内酯组心肌组织内丙二醛(MDA)表达较对照组升高,超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)含量较对照组降低;螺内酯组心肌组织内MDA表达低于再灌注组,SOD、GSH-PX含量高于再灌注组(P<0.05)。再灌注组、螺内酯组心肌与血浆白细胞介素(IL)-6、高迁移率族蛋白B1(HMGB1)表达均高于对照组;螺内酯组心肌与血浆IL-6、HMGB1表达均低于再灌注组(P<0.05)。再灌注组、螺内酯组心肌HMGB1 mRNA、Toll样受体4(TLR4)mRNA表达高于对照组;螺内酯组心肌HMGB1 mRNA、TLR4 mRNA表达低于再灌注组(P<0.05)。结论:肢体缺血再灌注后常导致心肌损伤,应用螺内酯治疗可减轻心肌损伤程度,可能是通过抑制氧化反应、抗炎症反应减轻心肌损伤程度,其作用信号传导机制主要是抑制HMGB1-TLR4信号通路。

Objective:To analyze the signal transduction mechanism of aldosterone receptor antagonist spironolactone in reducing myocardial injury caused by limb ischemia-reperfusion.Methods:Thirty healthy male rats were randomly divided into control group(10 rats,normal feeding),reperfusion group(10 rats,establishment of limb ischemia-reperfusion rat model),and spironolactone group(10 rats,spironolactone was given before establishing the model).The myocardial injury index,inflammatory response and oxidative stress were detected in 3 groups of rats.Results:The apoptosis rates of cardiomyocytes were(5.28±1.05)%,(185.47±35.85)%,(75.25±24.19)%respectively in the control group,the reperfusion group and the spironolactone group,with statistically significant differences between the three groups(P<0.05).Compared with the control group,serum creatine kinase(CK),creatine kinase isoenzyme(CK-MB),and cardiac troponin I(cTnI)were increased in the reperfusion group and the spironolactone group,serum cTnI,CK,and CK-MB were decreased in the spironolactone group more than those in the reperfusion group(P<0.05).Compared with the control group,the expression of malondialdehyde(MDA)in the myocardial tissue was increased in the perfusion group and the spironolactone group,the content of superoxide dismutase(SOD)and glutathione peroxidase(GSH-PX)were decreased.The expression of MDA in myocardial tissue was decreased in the spironolactone group more than that in the reperfusion group,and the contents of SOD and GSH-PX were increased more than those in the reperfusion group(P<0.05).Compared with the control group,the expressions of interleukin(IL)-6 and high mobility group protein B1(HMGB1)in the myocardium and plasma of the reperfusion group and spironolactone group were increased,the expressions of IL-6 and HMGB1 in the myocardium and plasma of the spironolactone group were decreased more than those of the reperfusion group(P<0.05).Compared with the control group,the expressions of HMGB1 mRNA and Toll-like receptor 4(TLR4)mRNA in the myocardial tissue were increased in the reperfusion group and spironolactone group,the expressions of HMGB1 mRNA and TLR4 mRNA in the myocardial tissue were decreased in the spironolactone group more than those in the reperfusion group(P<0.05).Conclusion:Myocardial injury was caused by limb ischemia-reperfusion.Spironolactone could reduce the degree of myocardial injury,probably by inhibiting oxidative and anti-inflammatory responses,and its action signaling pathway was related mainly inhibition of HMGB1-TLR4 signaling channel.