Doxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. Doxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. Semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.

中文翻译：

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索马鲁肽通过改善 BNIP3 介导的线粒体功能障碍来减轻阿霉素诱导的心脏毒性


阿霉素是一种强效的癌症化疗药物，但由于其潜在的心脏毒性，其使用受到限制。索马鲁肽（SEMA）是一种新型胰高血糖素样肽-1（GLP-1）类似物，在糖尿病治疗中受到广泛关注。然而，越来越多的证据强调了它对心脏功能的潜在治疗益处。因此，本研究的目的是检查索马鲁肽在改善阿霉素引起的心脏毒性方面的功效。阿霉素诱导的心脏毒性是研究心脏功能的既定模型。通过经胸超声心动图和有创血流动力学监测研究心脏功能。结果表明，索马鲁肽可显着改善阿霉素引起的心功能障碍。 RNA测序表明，这是削弱索马鲁肽在阿霉素诱导的心脏毒性中的保护作用的候选基因。为了确定 BNIP3 对索马鲁肽在阿霉素诱导的心脏毒性中的作用，将具有表达心肌肌钙蛋白 T (cTnT) 启动子的腺相关病毒血清型 9 (AAV9) 启动子的 BNIP3 注射到 C57/BL6J 小鼠的尾静脉中以过表达 BNIP3，特别是在心里。 BNIP3 的过度表达阻止了索马鲁肽引起的心脏功能的改善。实验表明，索马鲁肽通过PI3K/AKT途径，降低线粒体中BNIP3的表达，改善线粒体功能。 Semaglutide 通过减少线粒体中 BNIP3 的表达，通过 PI3K/AKT 途径改善多柔比星诱导的线粒体和心脏功能障碍。线粒体功能的改善减少了阿霉素介导的心脏损伤并改善了心脏功能。 因此，索马鲁肽是减少阿霉素引起的急性心脏毒性的潜在疗法。