Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, Thailand.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, Thailand.
Transl Res. 2022 May;243:33-51. doi: 10.1016/j.trsl.2021.12.005. Epub 2021 Dec 15.
The balance between cardiac sympathetic and parasympathetic activities has been intricately linked to mitochondrial function, cellular oxidative status, and immunomodulation in healthy and diseased myocardium. Cardiac autonomic neuropathy, along with the associated mitochondrial and cellular dysfunction, is an important pathophysiological feature of doxorubicin-induced cardiotoxicity (DIC). We tested the hypothesis that autonomic modulation by activation of acetylcholine receptors (AChR) effectively attenuates DIC. Rats were divided into control (0.9% sodium chloride solution) and doxorubicin groups (DOX, 3 mg/kg/d, 6 doses). Rats in the DOX group were equally subdivided into 4 interventional groups and treated for 30 days: vehicle, α7 nicotinic receptor agonist (PNU: PNU-282987, 3 mg/kg/d), muscarinic receptor agonist (BET: bethanechol, 12 mg/kg/d), and combined α7nAChR and mAChR agonists group (COM). Cardiac biochemical and functional analyses were done. The results show that AChR agonists protected the heart against DIC via improving mitochondrial and cardiac function, which was accompanied by reducing mitochondrial oxidative damage, apoptosis, and inflammation. Strikingly, PNU and BET exerted cardioprotection through different molecular pathways. PNU-mediated α7nAChR activation promoted mitochondrial fusion via upregulation of Mfn1-2 and attenuated DOX-induced autophagy. Contrarily, activation of mAChR by BET attenuated mitochondrial fission and mitophagy. The in vitro experiments confirmed the cytoprotective effects of AChR activation in DOX-treated H9c2 cells without compromising the anticancer effect of DOX in cancer cells. In conclusion, α7nAChR and mAChR agonists exerted cardioprotection against DIC via rebalancing autonomic function, improving mitochondrial function, reducing oxidative stress, and decreased cardiomyocyte apoptosis and inflammation, leading to improved cardiac function.
心脏交感和副交感活动的平衡与线粒体功能、细胞氧化状态和健康及患病心肌的免疫调节密切相关。心脏自主神经病变以及相关的线粒体和细胞功能障碍是多柔比星诱导的心脏毒性 (DIC) 的重要病理生理特征。我们检验了通过激活乙酰胆碱受体 (AChR) 调节自主神经可以有效减轻 DIC 的假说。将大鼠分为对照组（0.9%氯化钠溶液）和多柔比星组（DOX，3mg/kg/d，6 次）。DOX 组大鼠再等分为 4 个干预组并治疗 30 天：载体、α7 烟碱型乙酰胆碱受体激动剂（PNU：PNU-282987，3mg/kg/d）、毒蕈碱型乙酰胆碱受体激动剂（BET：氨甲酰胆碱，12mg/kg/d）和联合 α7nAChR 和 mAChR 激动剂组（COM）。进行心脏生化和功能分析。结果表明，AChR 激动剂通过改善线粒体和心脏功能来保护心脏免受 DIC 的侵害，同时减少线粒体氧化损伤、凋亡和炎症。值得注意的是，PNU 和 BET 通过不同的分子途径发挥心脏保护作用。PNU 介导的α7nAChR 激活通过上调 Mfn1-2 促进线粒体融合，并减轻 DOX 诱导的自噬。相反，BET 激活 mAChR 可减轻线粒体裂变和噬线粒体。体外实验证实了 AChR 激活在 DOX 处理的 H9c2 细胞中的细胞保护作用，而不影响 DOX 在癌细胞中的抗癌作用。总之，α7nAChR 和 mAChR 激动剂通过平衡自主神经功能、改善线粒体功能、减少氧化应激、减少心肌细胞凋亡和炎症来发挥 DIC 心脏保护作用，从而改善心脏功能。
