Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai 50200, Thailand.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai 50200, Thailand.
Toxicol Appl Pharmacol. 2024 Oct;491:117074. doi: 10.1016/j.taap.2024.117074. Epub 2024 Aug 20.
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.
尽管曲妥珠单抗在治疗人表皮生长因子受体 2 阳性癌症方面具有疗效，但曲妥珠单抗诱导的心脏毒性（TIC）已成为一个日益受到关注的问题。由于成年心脏中心肌细胞的再生和增殖能力有限，细胞死亡是心血管疾病的主要原因。迷走神经刺激（VNS）对心脏自主神经的调节已在多种心脏病模型中显示出心脏保护作用，而 VNS 对 TIC 的作用及其潜在机制尚未得到证实。本研究将 40 只成年雄性 Wistar 大鼠分为 5 组：（i）无 VNS 的对照组（CSham），（ii）无 VNS 的曲妥珠单抗组（TSham），（iii）曲妥珠单抗+VNS 组（TVNS），（iv）曲妥珠单抗+VNS+mAChR 阻滞剂（阿托品；1mg/kg/天，ip，TVNS+Atro）组，和（v）曲妥珠单抗+VNS+nAChR 阻滞剂（美加明；7.5mg/kg/天，ip，TVNS+Mec）组。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（包括凋亡、自噬缺陷、细胞焦亡和铁死亡）导致心脏功能障碍，VNS 可显著缓解这些变化。然而，mAChR 和 nAChR 阻滞剂显著抑制了 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 可拮抗 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 通过平衡自主神经活动、改善线粒体功能和心肌细胞死亡来预防 TIC，通过 mAChR 和 nAChR 的激活发挥作用。本研究为 VNS 的潜在治疗提供了新的视角，也为 TIC 患者提供了其他潜在的药物治疗选择。
