Qiu Q F, Peng C, Li Z Y, Xu X, Xi H S, Liu T Y, Tan W P, Huang J X, Zhou L P, Wang Y Y, Jiang H
Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Autonomic Nervous System Modulation, Cardiac Autonomic Nervous System Research Center of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
Zhonghua Xin Xue Guan Bing Za Zhi. 2024 Jul 24;52(7):791-797. doi: 10.3760/cma.j.cn112148-20240316-00148.
To investigate the effect of tocilizumab (TCZ) on ventricular arrhythmias (VAs) after myocardial infarction (MI) in Sprague-Dawley rats and explore its potential mechanism. The random number table method was used to divide 32 adult male Sprague-Dawley rats into 4 groups: Sham group, TCZ group, MI group and MI+TCZ group, with 8 rats in each group. The MI model was established by ligation of the left anterior descending branch of the coronary artery in the MI and MI+TCZ groups, and only sutured without ligation in the Sham and TCZ groups. TCZ was injected into the left superior cervical ganglion (SCG) of rats in the TCZ and MI+TCZ groups after successful modeling or sham operation, and the same amount of normal saline was injected in the Sham and MI groups. 24 h after successful modeling, ECG of rats in each group was recorded, heart rate variability (HRV, including low frequency power (LF), high frequency power (HF), LF/HF ratio), QT interval, QTc interval were calculated, and left ventricular effective refractory period (ERP) and VA inducibility were measured. Myocardial infarct size and tissue changes were observed with triphenyl tetrazolium chloride staining and HE staining. Real-time PCR analysis was used to detect the messager RNA (mRNA) expression of interleukin-6 (IL-6) and signal transducer and activator of transcription (STAT) 3 in SCG and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in myocardial infarction periphery. The expression of c-fos in SCG was detected by immunofluorescence staining. Compared with Sham group and MI+TCZ group, rats in MI group had higher LF and LF/HF ratio, longer QT interval and QTc interval, more VAs induced, lower HF and shorter ERP ( all<0.05). Triphenyl tetrazolium chloride staining and HE staining showed that rats in the Sham and TCZ groups had normal myocardial tissue structure, those in the MI group had severe myocardial injury, and those in the MI+TCZ group had less myocardial injury than those in the MI group. Real-ime PCR analysis showed that compared with Sham group and MI+TCZ group, mRNA expression levels of IL-6 and STAT3 in SCG of rats in MI group were higher, and mRNA expression level of myocardial Kcnd2 was lower ( all<0.05). Immunofluorescence staining showed that the content of c-fos in SCG of rats in MI group was higher than that of Sham group and MI+TCZ group ( all<0.05). TCZ may reduce neural activity of the SCG after MI by inhibiting the IL-6/STAT3 signaling pathway, thereby alleviating myocardial injury and inhibiting VAs.
探讨托珠单抗（TCZ）对Sprague-Dawley大鼠心肌梗死（MI）后室性心律失常（VA）的影响，并探讨其潜在机制。采用随机数字表法将32只成年雄性Sprague-Dawley大鼠分为4组：假手术组、TCZ组、MI组和MI + TCZ组，每组8只。MI组和MI + TCZ组通过结扎冠状动脉左前降支建立MI模型，假手术组和TCZ组仅缝合不结扎。建模成功或假手术后，向TCZ组和MI + TCZ组大鼠的左颈上神经节（SCG）注射TCZ，假手术组和MI组注射等量的生理盐水。建模成功后24 h，记录每组大鼠的心电图，计算心率变异性（HRV，包括低频功率（LF）、高频功率（HF）、LF/HF比值）、QT间期、QTc间期，测量左心室有效不应期（ERP）和VA诱发率。用三苯基四氮唑氯化物染色和HE染色观察心肌梗死面积和组织变化。采用实时荧光定量PCR分析检测SCG中白细胞介素-6（IL-6）和信号转导子与转录激活子（STAT）3以及心肌梗死周边区域钾离子电压门控通道亚家族D成员2（Kcnd2）的信使核糖核酸（mRNA）表达。通过免疫荧光染色检测SCG中c-fos的表达。与假手术组和MI + TCZ组相比，MI组大鼠的LF和LF/HF比值更高，QT间期和QTc间期更长，诱发的VA更多，HF更低，ERP更短（均P<0.05）。三苯基四氮唑氯化物染色和HE染色显示，假手术组和TCZ组大鼠心肌组织结构正常，MI组大鼠心肌损伤严重，MI + TCZ组大鼠心肌损伤程度低于MI组。实时荧光定量PCR分析显示，与假手术组和MI + TCZ组相比，MI组大鼠SCG中IL-6和STAT3的mRNA表达水平更高，心肌Kcnd2的mRNA表达水平更低（均P<0.05）。免疫荧光染色显示，MI组大鼠SCG中c-fos的含量高于假手术组和MI + TCZ组（均P<0.05）。TCZ可能通过抑制IL-6/STAT3信号通路降低MI后SCG的神经活性，从而减轻心肌损伤并抑制VA。
