Lv Meng, Yang Ding, Ji Xiaodi, Lou Lixia, Nie Bo, Zhao Jiuli, Wu Aiming, Zhao Mingjing
Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China.
Evid Based Complement Alternat Med. 2022 Sep 29;2022:2022970. doi: 10.1155/2022/2022970. eCollection 2022.
Myocardial infarction (MI) is an acute and serious cardiovascular disease. Arrhythmia after MI can lead to sudden cardiac death, which seriously affects the survival outcome of patients. WenXin KeLi is a Chinese patent medicine for the treatment of arrhythmia in a clinic, which can significantly improve symptoms of palpitation and play an important role in reducing the risk of arrhythmia after MI. In this study, we aimed to explore the pharmacological mechanism of WenXin KeLi in protecting the heart.
The MI model was established by ligating the left coronary artery and the ventricular fibrillation threshold (VFT) was measured by electrical stimulation. The expression of connexin43 (CX43) and autophagy-related protein were measured by Western Blot, and correlation analysis was conducted to study the relationship between cardiac autophagy, CX43, and arrhythmia in rats after MI. The effects of WenXin KeLi on arrhythmia, cardiac structure, and function in MI rats were respectively observed by electrical stimulation, cardiac gross section, Masson staining, and cardiac ultrasound. The effects of WenXin KeLi on the expression of phosphoinositide 3 kinase-protein kinase B-mammalian targets of rapamycin (PI3K-AKT-mTOR) autophagy pathway and CX43 were observed by Western Blot.
After 4 weeks of MI, the VFT in the model group was significantly reduced, the expression levels of yeast ATG6 homolog (Beclin1), microtubule-associated protein 1A/1B-light chain 3 (LC3II/LC3I), and p-CX43 (S368) significantly increased, the expression of sequestosome-1(P62) and CX43 significantly decreased. LC3II/LC3I and Beclin1 expression were significantly negatively correlated with the VFT, and the expression of P62 and CX43 were significantly positively correlated with the VFT. LC3II/LC3I and Beclin1 expression were negatively correlated with CX43 expression, while P62 expression was positively correlated with CX43 expression. WenXin KeLi could significantly increase the VFT, reduce the deposition of collagen fibers, and increase the index levels of the left ventricular end-diastolic anterior wall (LVEDAW), interventricular septum end-diastolic (IVSED), left ventricular end-systolic anterior wall (LVESAW), interventricular septum end-systolic (IVSES), left ventricular end-diastolic posterior wall (LVEDPW), left ventricular end-systolic posterior wall (LVESPW), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduce the index levels of the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). WenXin KeLi could increase the expression of CX43, P62, AKT, p-PI3K, p-AKT (308), p-AKT (473), and p-mTOR and decrease the expression of LC3II/LC3I and Beclin1.
WenXin KeLi can activate the PI3K-AKT-mTOR signaling pathway, improve cardiac autophagy and Cx43 expression in rats after MI, reduce the risk of arrhythmia after MI, and play a cardioprotective role.
心肌梗死（MI）是一种急性严重的心血管疾病。心肌梗死后的心律失常可导致心源性猝死，严重影响患者的生存结局。稳心颗粒是临床上用于治疗心律失常的一种中成药，能显著改善心悸症状，在降低心肌梗死后心律失常风险方面发挥重要作用。在本研究中，我们旨在探讨稳心颗粒保护心脏的药理机制。
通过结扎左冠状动脉建立心肌梗死模型，采用电刺激测量心室颤动阈值（VFT）。采用蛋白质免疫印迹法检测连接蛋白43（CX43）和自噬相关蛋白的表达，并进行相关性分析以研究心肌梗死后大鼠心脏自噬、CX43与心律失常之间的关系。通过电刺激、心脏大体切片、Masson染色和心脏超声分别观察稳心颗粒对心肌梗死大鼠心律失常、心脏结构和功能的影响。采用蛋白质免疫印迹法观察稳心颗粒对磷脂酰肌醇3激酶-蛋白激酶B-雷帕霉素哺乳动物靶蛋白（PI3K-AKT-mTOR）自噬途径和CX43表达的影响。
心肌梗死后4周，模型组VFT显著降低，酵母自噬相关基因6同源物（Beclin1）、微管相关蛋白1A/1B轻链3（LC3II/LC3I）和磷酸化CX43（S368）表达水平显著升高，聚集体蛋白1（P62）和CX43表达显著降低。LC3II/LC3I和Beclin1表达与VFT呈显著负相关，P62和CX43表达与VFT呈显著正相关。LC3II/LC3I和Beclin1表达与CX43表达呈负相关，而P62表达与CX43表达呈正相关。稳心颗粒可显著提高VFT，减少胶原纤维沉积，增加左心室舒张末期前壁（LVEDAW）、室间隔舒张末期（IVSED）、左心室收缩末期前壁（LVESAW）、室间隔收缩末期（IVSES）、左心室舒张末期后壁（LVEDPW）、左心室收缩末期后壁（LVESPW）、左心室射血分数（LVEF）和左心室短轴缩短率（LVFS）的指标水平，并降低左心室舒张末期内径（LVEDD）、左心室收缩末期内径（LVESD）、左心室舒张末期容积（LVEDV）和左心室收缩末期容积（LVESV）的指标水平。稳心颗粒可增加CX43、P62、AKT、磷酸化PI3K、磷酸化AKT（308）、磷酸化AKT（473）和磷酸化mTOR的表达，并降低LC3II/LC3I和Beclin1的表达。
稳心颗粒可激活PI3K-AKT-mTOR信号通路，改善心肌梗死后大鼠心脏自噬和Cx43表达，降低心肌梗死后心律失常风险，发挥心脏保护作用。
