摘要
目的探讨C-C趋化因子受体9(CCR9)/C-C基序趋化因子配体25(CCL25)轴对阿霉素(DOX)诱导的心脏毒性的影响.方法将60只野生型C57BL/6J小鼠随机分为四组:对照组(CTL组,n=15)、腹腔注射阿霉素组(DOX组,n=15)、腹腔注射阿霉素+尾静脉注射生理盐水组(DOX+NS组,n=15)、腹腔注射阿霉素+尾静脉注射抗CCL25中和抗体组(DOX+anti-CCL25组,n=15);造模7天后,超声心动图评估小鼠心功能;使用程序化电刺激记录小鼠在体心脏的单向动作电位时程(MAPD)、有效不应期(ERP)、电交替(ALT)阈值和室性心律失常的诱发率.结果与CTL组相比,DOX组左室射血分数(LVEF)和短轴缩短分数(FS)显著降低,左心室舒张末期内径(LVIDd)和左心室收缩末期内径(LVIDs)显著增加(P均<0.05);30%单向动作电位时程(MAPD30)、MAPD50、MAPD70、MAPD90和动作电位复极化时限三角测量值(triangulation)均延长,ERP延长,ALT阈值降低(P均<0.05);10 V和20 V Burst刺激下室性心律失常的诱发率和S1S1程序化刺激下室性心律失常的诱发率均显著升高(P均<0.008);与DOX组相比,DOX+anti-CCL25组LVEF和FS显著升高,LVIDd和LVIDs减小(P均<0.05);MAPD70、MAPD90、Triangulation和ERP缩短(P均<0.05).结论DOX导致小鼠心脏结构重构和电重构,发生室性心律失常的易感性增加,抗CCL25中和抗体可以明显改善DOX小鼠心脏的结构重构和电重构,CCR9/CCL25通路在阿霉素诱导的心脏毒性中有重要作用.
Objective To investigate the effects of the C-C chemokine receptor type 9(CCR9)/C-C motif chemo-kine ligand 25(CCL25)axis on doxorubicin(DOX)-induced cardiotoxicity.Methods Sixty wild-type C57BL/6J mice were randomly divided into four groups:the control group(CTL group,n=15),the intraperitoneal injection of doxorubicin group(DOX group,n=15),the intraperitoneal injection of doxorubicin+tail vein injection of normal saline group(DOX+NS group,n=15),and the intraperitoneal injection of doxorubicin+tail vein injection of anti-CCL25 neutralizing antibody group(DOX+anti-CCL25 group,n=15).Seven days after modeling,cardiac function was evaluated by echocardiography.Monophasic action potential duration(MAPD),effective refractory period(ERP),alternans(ALT)threshold,and the incidence of ventricular arrhythmias were recorded in vivo using pro-grammed electrical stimulation.Results Compared to the CTL group,the DOX group showed a significant de-crease in left ventricular ejection fraction(LVEF)and fractional shortening(FS),and a significant increase in left ventricular end-diastolic diameter(LVIDd)and left ventricular end-systolic diameter(LVIDs)(all P<0.05).The duration of the unidirectional action potential at 30%(MAPD30),50%(MAPD50),70%(MAPD70),and 90%(MAPD90),as well as the triangulation of action potential repolarization time,were all prolonged,the ERP was ex-tended,and the ALT threshold was reduced(all P<0.05).The inducibility of ventricular arrhythmias under 10 V and 20 V burst stimulation and under S1S1 programmed stimulation was significantly increased(all P<0.008).Com-pared to the DOX group,the DOX+anti-CCL25 group showed significant increases in LVEF and FS,with signifi-cant decreases in LVIDd and LVIDs(all P<0.05).MAPD70,MAPD90,triangulation,and ERP were shortened.Conclusion DOX induces cardiac structural and electrical remodeling in mice,increasing the susceptibility to ventric-ular arrhythmias.Anti-CCL25 neutralizing antibodies significantly improve the structural and electrical remodeling of the heart in DOX-treated mice.The CCR9/CCL25 axis plays an important role in DOX-induced cardiotoxicity.
作者
李涵晟
王美伦
林泽阳
王宇恒
宋涛
黄燕
LI Hansheng;WANG Meilun;LIN Zeyang;WANG Yuheng;SONG Tao;HUANG Yan(Department of Cardiology,Renmin Hospital of Wuhan University,Cardiovascular Research Institute of Wuhan University,Hubei Key Laboratory of Cardiology,Wuhan 430060,China;School of Electronic Information,WuhanUniversity,Wuhan430072,China)
出处
《中国心脏起搏与心电生理杂志》
2025年第3期217-222,共6页
Chinese Journal of Cardiac Pacing and Electrophysiology
基金
国家自然科学基金资助项目(82100331)
湖北省自然科学基金(2023AFB797,2023AFB806)
武汉市知识创新专项项目(2022020801020484)
中央高校自主科研项目(2042019kf0058)
