Acetylcholine receptor agonists provide cardioprotection in doxorubicin-induced cardiotoxicity via modulating muscarinic M2 and α7 nicotinic receptor expression.

Translational research : the journal of laboratory and clinical medicine 2022 May

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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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Chayodom Maneechote, Nattayaporn Apaijai, Titikorn Chunchai, Busarin Arunsak, Krekwit Shinlapawittayatorn, Siriporn C Chattipakorn, Nipon Chattipakorn. Acetylcholine receptor agonists provide cardioprotection in doxorubicin-induced cardiotoxicity via modulating muscarinic M2 and α7 nicotinic receptor expression. Translational research : the journal of laboratory and clinical medicine. 2022 May;243:33-51