Division of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
Department of Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
ESC Heart Fail. 2024 Apr;11(2):1182-1193. doi: 10.1002/ehf2.14686. Epub 2024 Jan 29.
The clinical application of doxorubicin (DOX), a potent anthracycline anticancer drug that effectively treats various malignancies, is limited by its side effects, such as cardiomyopathy. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that can be secreted and is a promising target for the reduction of DOX-induced inflammation and oxidative stress. We aimed to investigate the protective role of secretory APE1/Ref-1 against DOX-induced cardiac injury.
Designated adenoviral preprotrypsin-leading sequence APE1/Ref-1 (Ad-PPTLS-APE1/Ref-1) was used to overexpress secretory APE1/Ref-1 and assess its role in preventing DOX-induced cardiomyopathy in vitro. Our findings revealed that exposure to secretory APE1/Ref-1 significantly decreased N-terminal pro-B-type natriuretic peptide levels in DOX-treated H9C2 cells. In addition, secretory APE1/Ref-1 reduced the severity of cardiomyocyte injury and apoptosis in both in vitro and in vivo DOX-induced cardiotoxicity models. The observed cardioprotective effects of secretory APE1/Ref-1 were mediated via inhibition of the p53 signalling pathway and enhancement of cell viability through attenuation of oxidative stress in DOX-treated cardiomyocytes.
Our study provides evidence that secretory APE1/Ref-1 has the potential to inhibit DOX-induced cardiac toxicity by inhibiting oxidative stress and p53 related apoptosis both in vitro and in vivo. These findings suggest that secretory APE1/Ref-1 supplementation is a promising strategy to attenuate DOX-induced cardiomyocyte damage in a preclinical model. Further clinical investigations are essential to validate the therapeutic efficacy and safety of the intervention in human subjects.
多柔比星（DOX）是一种有效的抗癌药物，能够有效治疗多种恶性肿瘤，但由于其副作用，如心肌病，其临床应用受到限制。脱嘌呤/脱嘧啶核酸内切酶 1/氧化还原因子-1（APE1/Ref-1）是一种多功能蛋白，可被分泌，是减少 DOX 诱导的炎症和氧化应激的有前途的靶点。我们旨在研究分泌型 APE1/Ref-1 对 DOX 诱导的心脏损伤的保护作用。
设计了表达分泌型 APE1/Ref-1 的腺病毒前脯氨酸丝氨酸蛋白酶原（Ad-PPTLS-APE1/Ref-1），用于评估其在预防 DOX 诱导的体外心肌病变中的作用。我们的研究结果表明，暴露于分泌型 APE1/Ref-1 可显著降低 DOX 处理的 H9C2 细胞中 N 末端 pro-B 型利钠肽水平。此外，分泌型 APE1/Ref-1 减少了体外和体内 DOX 诱导的心脏毒性模型中心肌细胞损伤和凋亡的严重程度。分泌型 APE1/Ref-1 的观察到的心脏保护作用是通过抑制 p53 信号通路和增强细胞活力来介导的，通过减轻 DOX 处理的心肌细胞中的氧化应激来实现。
我们的研究提供了证据表明，分泌型 APE1/Ref-1 通过抑制氧化应激和 p53 相关的凋亡，具有抑制 DOX 诱导的心脏毒性的潜力，无论是在体外还是体内。这些发现表明，分泌型 APE1/Ref-1 的补充是一种有前途的策略，可以减轻临床前模型中 DOX 诱导的心肌细胞损伤。需要进一步的临床研究来验证该干预措施在人体中的治疗效果和安全性。
