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

Yifan CHEN; Yihui SHEN; Leilei CHENG; Jinyi LIN; Hui ZHANG; Xuejun WANG; Yuchen XU; Jian ZHANG; Junbo GE

doi:10.19401/j.cnki.1007-3639.2022.10.002

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

Specialists'Article | 更新时间：2025-12-31

- Different preventive effects of four cardioprotective agents on mice with adriamycin-induced cardiotoxicity
- China Oncology Vol. 32, Issue 10, Pages: 936-947(2022)
- 作者机构：
  
  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
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.10.002
  CLC： R730.59
- Published Online：30 October 2022，
- 稿件说明：
移动端阅览
Yifan CHEN, Yihui SHEN, Leilei CHENG, et al. Different preventive effects of four cardioprotective agents on mice with adriamycin-induced cardiotoxicity[J]. China Oncology, 2022, 32(10): 936-947.
DOI：

Yifan CHEN, Yihui SHEN, Leilei CHENG, et al. Different preventive effects of four cardioprotective agents on mice with adriamycin-induced cardiotoxicity[J]. China Oncology, 2022, 32(10): 936-947. DOI： 10.19401/j.cnki.1007-3639.2022.10.002.

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28.8 mg/kg，缬沙坦31.2 mg/kg）和卡维地洛5 mg/kg，以每日每只0.2 mL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分数（left ventricular ejection fraction，LVEF）（65.1%±3.8%

63.5%±4.6%，61.6%±4.1%，62.1%±5.2%，

0.05）和缩短分数（fractional shortening，FS）（34.2%±3.7%、33.9%±3.3%、32.6%±2.8%和33.0%±3.6%，

0.05），减轻心脏纤维化；贝那普利和沙库巴曲缬沙坦在限制心脏大小、心脏与胫骨长度之比（heart weight to tibia length，HW/TL）和保持心肌细胞横截面积（cardiomyocyte cross-sectional area，CSA）方面具有明显的效果；阿托伐他汀兼具中等水平的抗凋亡以及抗炎功效；卡维地洛的抗炎作用为4种药物之首。

结论：

本研究比较了不同药物对阿霉素诱导的心肌病的保护作用并初步探索了潜在机制。未来大规模临床研究可进一步探索患者层面不同心脏保护药物缓解阿霉素诱导的心脏毒性的潜能。

Abstract

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 b

enazepril

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/6 mice 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-induced cell apoptosis and modulated the expressions of Bcl-2 and Bax proteins. They also attenuated adriamycin-mediated expressions of proinflammatory cytokines

tumor necrosis factor-α (TNF-α)

interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the myocardium.

Furthermore

sacubitril/valsartan not only enormously improved left ventricular ejection fraction (LVEF) (65.1%±3.8%

63.5%±4.6%

61.6%±4.1% and 62.1%±5.2%

0.05) and fractional shortening (FS) (34.2%±3.7%

33.9%±3.3%

32.6%±2.8% and 33.0%±3.6%

0.05)

but also alleviated cardiac fibrosis compared with the other three medicaments. Benazepril and sacubitril/valsartan manifested curative effect in limiting the size of the heart

the ratio of heart weight to tibia length (HW/TL)

and cardiomyocyte cross-sectional area (CSA). Atorvastatin owned a moderate level of anti-apoptotic and anti-inflammatory properties. Among these medications

carvedilol provided the best anti-inflammatory effects.

Conclusion:

We compared different agents for their effects on the protection of adriamycin-induced cardiomyopathy and preliminarily explored underlying mechanisms. In the future

large-scale clinical studies could further explore the potential of different cardioprotective drugs at the patient level to alleviate adriamycin-induced cardiotoxicities.

关键词

Keywords

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Huan QIN

Jie WANG

Jie YANG

Yingjie HUA

Huijuan QU

Honghai JI

Xiaofei XU

Lixia ZHANG

Related Institution

School of Stomatology, Shandong Second Medical University

Shouguang Stomatological Hospital

Department of Stomatology, Affiliated Hospital of Shandong Second Medical University

Graduate School, Hebei Medical University

Fourth Department of Oncology, Hebei General Hospital

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