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.
Cell Mol Life Sci. 2022 Dec 30;80(1):21. doi: 10.1007/s00018-022-04678-4.
The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.
程序性细胞死亡的失常，包括与自噬/线粒体自噬、细胞凋亡、坏死性凋亡、细胞焦亡和铁死亡相关的细胞死亡，可在多柔比星诱导的心脏毒性（DIC）的发展和进展中观察到。迷走神经刺激（VNS）已被证明可以通过在多种病理条件下释放神经递质乙酰胆碱（ACh）来发挥心肌细胞死亡的心脏保护作用。然而，VNS 对抗 DIC 的作用及其潜在机制从未被研究过。40 只成年雄性 Wistar 大鼠被分为 5 个实验组：（i）无 VNS 的对照组（CSham）组，（ii）无 VNS 的多柔比星组（DSham）组，（iii）多柔比星+VNS 组（DVNS）组，（iv）多柔比星+VNS+mAChR 拮抗剂（阿托品；1mg/kg/天，ip，DVNS+Atro）组，和（v）多柔比星+VNS+nAChR 拮抗剂（美加明；7.5mg/kg/天，ip，DVNS+Mec）组。我们的结果表明，多柔比星损伤通过损害心脏自主平衡、降低线粒体功能、失衡线粒体动力学以及加剧包括自噬/线粒体自噬、细胞凋亡、坏死性凋亡、细胞焦亡和铁死亡在内的心肌细胞死亡，导致左心室（LV）功能障碍。然而，VNS 治疗改善了心脏线粒体和自主神经功能，并抑制了过度的自噬、细胞凋亡、坏死性凋亡、细胞焦亡和铁死亡，从而改善了 LV 功能。与此一致，ACh 有效地提高了多柔比星处理的 H9c2 细胞的细胞活力并抑制了细胞细胞毒性。相比之下，毒蕈碱（mAChR）或烟碱型乙酰胆碱受体（nAChR）的抑制剂完全消除了 VNS 和乙酰胆碱介导的有利作用。这些发现表明，VNS 通过激活 mAChR 和 nAChR 发挥对抗多柔比星诱导的心肌细胞死亡的心脏保护作用。
