尽管曲妥珠单抗对人表皮生长因子受体 2 阳性癌症治疗有效，但其引起的心脏毒性 (TIC) 已成为越来越令人担忧的问题。由于成人心脏缺乏心肌细胞再生和增殖，细胞死亡会显着导致心血管疾病。通过迷走神经刺激 (VNS) 进行的心脏自主调节已在多种心脏病模型中显示出心脏保护作用，但 VNS 及其针对 TIC 的潜在机制尚未被发现。将四十只成年雄性 Wistar 大鼠分为 5 组：（i）无 VNS 的对照（CSham）组，（ii）无 VNS 的曲妥珠单抗（4mg/kg/天，腹膜内注射）（TSham）组，（iii）曲妥珠单抗 VNS（TVNS）组) 组，(iv) 曲妥珠单抗 VNS mAChR 阻滞剂（阿托品；1mg/kg/天，腹膜内，TVNS Atro）组，以及 (v) 曲妥珠单抗 VNS nAChR 阻滞剂（美加明；7.5mg/kg/天，腹膜内，TVNS Mec）团体。我们的结果表明，曲妥珠单抗通过增加自主神经功能障碍、线粒体功能障碍/动力学失衡和心肌细胞死亡（包括细胞凋亡、自噬缺陷、细胞焦亡和铁死亡）来诱导心脏功能障碍，而 VNS 可以显着减轻这些死亡。然而，mAChR 和 nAChR 阻滞剂显着抑制 VNS 对心脏自主神经功能障碍、线粒体功能障碍、心肌细胞凋亡、细胞焦亡和铁死亡的有益作用。只有 nAChR 可以抵消 VNS 对心脏线粒体动力学失衡和自噬不足的保护作用。因此，VNS 通过重新平衡自主神经活动、通过 mAChR 和 nAChR 激活改善线粒体功能障碍和心肌细胞死亡来预防 TIC。目前的研究提供了一个新的视角来阐明 VNS 的潜在治疗方法，从而也为 TIC 患者提供其他药物治疗的希望。版权所有 © 2024。由 Elsevier Inc. 出版。

Despite its efficacy in human epidermal growth factor receptor 2 positive cancer treatment, trastuzumab-induced cardiotoxicity (TIC) has become a growing concern. Due to the lack of cardiomyocyte regeneration and proliferation in adult heart, cell death significantly contributes to cardiovascular diseases. Cardiac autonomic modulation by vagus nerve stimulation (VNS) has shown cardioprotective effects in several heart disease models, while the effects of VNS and its underlying mechanisms against TIC have not been found. Forty adult male Wistar rats were divided into 5 groups: (i) control without VNS (CSham) group, (ii) trastuzumab (4 mg/kg/day, i.p.) without VNS (TSham) group, (iii) trastuzumab + VNS (TVNS) group, (iv) trastuzumab + VNS + mAChR blocker (atropine; 1 mg/kg/day, ip, TVNS + Atro) group, and (v) trastuzumab + VNS + nAChR blocker (mecamylamine; 7.5 mg/kg/day, ip, TVNS + Mec) group. Our results showed that trastuzumab induced cardiac dysfunction by increasing autonomic dysfunction, mitochondrial dysfunction/dynamics imbalance, and cardiomyocyte death including apoptosis, autophagic deficiency, pyroptosis, and ferroptosis, which were notably alleviated by VNS. However, mAChR and nAChR blockers significantly inhibited the beneficial effects of VNS on cardiac autonomic dysfunction, mitochondrial dysfunction, cardiomyocyte apoptosis, pyroptosis, and ferroptosis. Only nAChR could counteract the protective effects of VNS on cardiac mitochondrial dynamics imbalance and autophagy insufficiency. Therefore, VNS prevented TIC by rebalancing autonomic activity, ameliorating mitochondrial dysfunction and cardiomyocyte death through mAChR and nAChR activation. The current study provides a novel perspective elucidating the potential treatment of VNS, thus also offering other pharmacological therapeutic promises in TIC patients.Copyright © 2024. Published by Elsevier Inc.