关键词: 阿霉素, 心脏毒性, 心肌病, 凋亡, 纤维化, 炎症

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 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/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%, P<0.05) and fractional shortening (FS) (34.2%±3.7%, 33.9%±3.3%, 32.6%±2.8% and 33.0%±3.6%, P<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.

Key words: Adriamycin, Cardiotoxicity, Cardiomyopathy, Apoptosis, Fibrosis, Inflammation