目的 探讨黄连碱抑制Ras同源基因家族成员（Rho）／Rho激酶（ROCK）通路对阿霉素诱导的心力衰竭大鼠心律失常及其心肌保护作用机制。方法 将SD大鼠随机分为对照组、模型组、黄连碱（3、12 mg/kg）组、美托洛尔组、黄连碱＋溶血磷脂酸组。检测大鼠左心室射血分数（LVEF）、左心室短轴缩短率（LVFS）、左心室舒张末期内径（LVEDD）、左心室收缩末期内径（LVESD）、室性早搏发生率、心率的变化；ELISA检测血清脑钠肽（BNP）、可溶性生长刺激表达基因2蛋白（ST2）水平；Masson染色检测心肌组织纤维化并评估心肌胶原容积分数（CVF）；试剂盒检测心肌组织肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6、IL-10水平及丙二醛（MDA）、还原型谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）、超氧化物歧化酶（SOD）水平；Western blotting检测心肌组织III型胶原蛋白（Collagen III）、α-平滑肌肌动蛋白（α-SMA）、Ras同源基因家族成员A（RhoA）、ROCK1、磷酸化肌球蛋白磷酸酶靶向亚基1（p-MYPT1）/MYPT1蛋白水平。结果 与模型组相比，黄连碱各剂量组LVEDD、LVESD、室性早搏发生率、心率、血清BNP、ST2水平、心肌组织TNF-α、IL-6、MDA水平及Collagen III、α-SMA、RhoA、ROCK1、p-MYPT1/MYPT1蛋白、CVF降低，胶原沉积减少，LVFS、LVEF、心肌组织IL-10、GSH/GSSG、SOD水平升高（P＜0.05）；溶血磷脂酸处理逆转了黄连碱对模型大鼠心肌纤维化、炎症反应、氧化应激及心律失常的改善作用。结论 黄连碱能够有效改善阿霉素诱导的心力衰竭大鼠心律失常及心功能，其作用机制可能与抑制Rho/ROCK通路，进而减轻心肌纤维化、炎症反应和氧化应激密切相关。

Objective To explore the mechanism of coptisine inhibiting the Rho/ROCK pathway on arrhythmia and myocardial protection in doxorubicin-induced heart failure rats. Methods SD Rats were randomly divided into control group, model group, coptisine (3, 12 mg/kg) group, metoprolol group, coptisine + lysophosphatidic acid group. The changes in LVEF, LVFS, LVEDD, LVESD, VPB incidence, and heart rate of rats were measured. ELISA was used to detect the serum levels of BNP and ST2. Masson staining for detecting myocardial tissue fibrosis and evaluating myocardial CVF. Commercial kits were used to determine the levels of TNF-α, IL-6, IL-10, MDA, GSH/GSSG, and SOD in myocardial tissue. Western blotting was employed to detect the protein expressions of Collagen III, α-SMA, RhoA, ROCK1, and p-MYPT1/MYPT1 in myocardial tissue. Results Compared with the model group, coptisine (3, 12 mg/kg) group exhibited significantly reduced LVEDD, LVESD,VPB incidence, HR, serum BNP and ST2 levels, myocardial TNF-α, IL-6 and MDA levels, and the protein expressions of Collagen III, α-SMA, RhoA, ROCK1, p-MYPT1/MYPT1, and CVF, with decreased collagen deposition. In contrast, LVFS, LVEF, and myocardial IL-10, GSH/GSSG, and SOD levels were significantly increased (P < 0.05). Treatment with lysophosphatidic acid reversed the ameliorating effects of coptisine on myocardial fibrosis, inflammatory response, oxidative stress, and arrhythmia in model rats. Conclusion Coptisine can effectively improve arrhythmia and cardiac function in doxorubicin-induced heart failure rats, and its mechanism of action may be closely related to inhibiting the Rho/ROCK pathway, thereby alleviating myocardial fibrosis, inflammatory response and oxidative stress.

R285.5

河南省科技发展计划（252300420107）