四种心脏保护药物对小鼠阿霉素诱导的心脏毒性的不同预防作用  

Different preventive effects of four cardioprotective agents on mice with adriamycin-induced cardiotoxicity

作　　者：陈怡帆 沈毅辉 程蕾蕾[2,3,4] 林瑾仪 张卉 汪雪君 许宇辰 张健 葛均波 CHEN Yifan;SHEN Yihui;CHENG Leilei;LIN Jinyi;ZHANG Hui;WANG Xuejun;XU Yuchen;ZHANG Jian;GE Junbo(Department of Cardiology,Zhongshan Hospital,Fudan University,Shanghai 200032,China;Shanghai Institute of Cardiovascular Diseases,Shanghai 200032,China;National Clinical Research Center for Interventional Medicine,Shanghai 200032,China;Department of Echocardiography,Zhongshan Hospital,Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学附属中山医院心内科,上海200032 [2]上海市心血管病研究所,上海200032 [3]国家放射与治疗临床医学研究中心,上海200032 [4]复旦大学附属中山医院心脏超声诊断科,上海200032

出　　处：《中国癌症杂志》2022年第10期936-947,共12页China Oncology

基　　金：国家自然科学基金(82170359)。

摘　　要：背景与目的:阿霉素又称多柔比星,是一种广泛使用的蒽环类抗肿瘤药物,但以扩张型心肌病和充血性心力衰竭为典型表现的心脏毒性限制了其更为广泛的临床应用。本研究旨在比较高血压、高脂血症和心肌病的常用心脏保护药物贝那普利、阿托伐他汀、沙库巴曲缬沙坦和卡维地洛对阿霉素诱导的心肌病的保护作用并初步探索其潜在机制。方法:将成年雄性C57BL/6小鼠分为:生理盐水组、阿霉素组、阿霉素+阿托伐他汀组(atorvastatin)、阿霉素+贝那普利组(benazepril)、阿霉素+沙库巴曲缬沙坦组(sacubitril/valsartan)和阿霉素+卡维地洛组(carvedilol)。除生理盐水组外,予腹膜内注射阿霉素溶液(每周4 mg/kg)共5周,建立阿霉素诱导的体内心肌病模型。各组每日分别予阿托伐他汀10 mg/kg、贝那普利10 mg/kg、沙库巴曲缬沙坦60 mg/kg(沙库巴曲28.8mg/kg,缬沙坦31.2 mg/kg)和卡维地洛5 mg/kg,以每日每只0.2mL的剂量灌胃预处理共6周。进行各组二维超声心动图、细胞凋亡、纤维化和炎症等分析。采用实时荧光定量聚合酶链反应(real-time fluorescence quantitative polymerase chain reaction,RTFQ-PCR)检测心肌细胞中总mRNA,采用蛋白质印迹法(Western blot)检测Bax和Bcl-2的表达水平。在4T1乳腺肿瘤细胞接种的BALB/c小鼠中,对以上不同的心脏保护药物进行治疗前后肿瘤体积和质量予以记录,评估心脏保护药物应用对肿瘤生长的影响。结果:这些心脏保护药物都有效地抑制了阿霉素引起的左心室功能障碍,改善了阿霉素相关的组织病理损伤,并皆能抑制阿霉素诱导的细胞凋亡和调节Bcl-2和Bax蛋白的表达,减少心肌细胞中阿霉素介导的促炎细胞因子、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-1β(interleukin-1β,IL-1β)和白细胞介素-6(interleukin-6,IL-6)的积累。与其他3种药物相比,沙库巴曲缬沙坦能显著提高左心室射血�Background and purpose: Adriamycin, also named as doxorubicin, is an effective antineoplastic anthracycline drug used worldwide. However, its cardiotoxicities characterized as dilated cardiomyopathy and congestive heart failure have limited its clinical application. This study aimed to compare the effects of benazepril, atorvastatin, sacubitril/valsartan and carvedilol on the protection of adriamycin-induced cardiomyopathy, which are commonly used as cardioprotective agents for hypertension,hyperlipidemia and cardiomyopathy, and then preliminarily explored the underlying mechanisms. Methods: Adult male C57BL/6mice were divided into saline, adriamycin, adriamycin+atorvastatin, adriamycin+benazepril, adriamycin+sacubitril/valsartan and adriamycin+carvedilol groups. In addition to the saline group, adriamycin solution(4 mg/kg per week) was injected intraperitoneally for 5 weeks to establish the dox-induced cardiomyopathy model in vivo. Different groups were pretreated with different cardioprotective agents 0.2 mL per day for each mouse by gavage for a total of 6 weeks. The dose was: atorvastatin 10 mg/kg per day, benazepril 10 mg/kg per day, sakubactro/valsartan 60 mg/kg per day(sakubactro 28.8 mg/kg per day, valsartan 31.2 mg/kg per day) and carvedilol 5 mg/kg per day, respectively. Two-dimensional echocardiography, cell apoptosis, fibrosis and inflammation markers were analyzed in these mice. Real-time fluorescence quantitative polymerase chain reaction(RTFQ-PCR) was used to detect the total mRNA in cardiomyocytes, and Western blot was used to detect the expression levels of Bax and Bcl-2. Among BALB/c mice inoculated with 4T1 breast tumor cells, the tumor volume and mass were studied before and after treatments with different cardioprotective drugs to evaluate the effects of cardioprotective drugs on tumor growth. Results: The data revealed that all these four cardioprotective agents effectively inhibited adriamycin-induced left ventricular dysfunction, ameliorated histopathological damage, suppressed adriamycin-

关 键 词：阿霉素 心脏毒性 心肌病 凋亡 纤维化 炎症 

分 类 号：R730.59[医药卫生—肿瘤]