利多卡因通过激活AMPK/SOCS3信号通路改善阿霉素引起的急性心肌损伤
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1.南京医科大学第二附属医院心血管外科;2.南京医科大学药理学系江苏省神经变性重点实验室

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国家自然科学基金(82170503);江苏省重点研发计划(社会发展)项目(BE2021749)


Lidocaine improves acute myocardial injury induced by doxorubicin by activating AMPK/SOCS3 signaling pathway
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National Natural Science Foundation of China (82170503); Jiangsu Province Key R & D Program (Social Development) Project (BE2021749)

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    摘要:

    目的:研究利多卡因(Lidocaine,LIDO)对阿霉素(doxorubicin,DOX)引起小鼠心脏损伤的治疗效果及作用机制。方法:32只SPF小鼠随机分为4组(n=8),分别为对照组、DOX组、DOX+LIDO组 、LIDO组,观察并检测各组小鼠体重、生存率、多普勒血流成像、心电图,血浆肌酸激酶同工酶(CreatineKinase-MB,CK-MB)、肌钙蛋白T(Centenary Translation of the New Testament,cTn-T),心肌组织中组织因子( tissue factor,TF)、基质金属蛋白酶9(matrix metalloprotein9, MMP-9 )、磷酸化磷酸腺苷活化蛋白激酶(phosphorylated Adenosine 5‘-monophosphate-activated protein kinase,p-AMPK)、缝隙连接蛋白(connexin43,Cx43)、细胞因子信号转导抑制因子3(Recombinant Suppressors Of Cytokine Signaling 3,SOCS3)的含量。结果:与DOX组相比,DOX+LIDO组小鼠体重、生存率增加,心率改善,QRS波时限及QT间期恢复正常,血浆CK-MB、cTn-T值处于正常区间,心脏恢复至正常大小,TF、MMP-9降低,心脏组织中p-AMPK、SOCS、Cx43表达增加。结论:利多卡因可改善阿霉素诱导的心脏毒性,主要通过上调AMPK从而上升SOCS3,导致Cx43表达上调。

    Abstract:

    Objective: To study the therapeutic effect and corresponding mechanism of lidocaine (Lidocaine, LIDO) on cardiac injury induced by doxorubicin (Doxorubicin, DOX) in mice. Methods: 32 SPF mice were randomly divided into 4 groups (n = 8). The model of acute myocardial injury was constructed by single intra-abdominal injection of DOX 20mg/kg. There were four groups: control group, DOX group, DOX+LIDO group, and LIDO group. The body weight, survival rate, Doppler flow imaging, electrocardiogram, levels of CK-MB, cTn-T, TF, MMP-9, p-AMPK, Cx43 and SOCS3 in each group were measured. Results: Compared with the DOX group, DOX + LIDO group of the mice showed increased body weight and survival, improved heart rate, normalized QRS duration and QT interval, plasma CK-MB and cTn-T values in the normal interval, heart recovery to normal size, decreased TF and MMP-9, and increased expression of p-AMPK, SOCS, and Cx43 in heart tissue. Conclusions: Lidocaine ameliorates doxorubicin-induced cardiotoxicity, possibly through increasing AMPK and subsequent SOCS3 expressions, resulting in Cx43 upregulation.

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  • 收稿日期:2023-03-10
  • 最后修改日期:2023-05-16
  • 录用日期:2023-08-09
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