Abstract 11231: Acetylcholine Receptor Agonists Exert Cardioprotection Against Trastuzumab-Induced Cardiotoxicity by Attenuating NLRP3/GSDMD-Mediated Pyroptosis

Abstract

Introduction: The most significant adverse effect of trastuzumab (TRZ) is cardiotoxicity. Multiple factors are involved in the pathogenesis of TRZ-induced cardiotoxicity (TIC), including mitochondrial dysfunction, inflammation, and pyroptosis. Although vagal modulation using acetylcholine receptors (AChR) agonists have been shown to exert cardioprotection in various heart diseases, the effects of AChR agonists against TIC have not been investigated. Hypothesis: We hypothesized that AChR agonists exert cardioprotective effects against TIC by attenuating cardiac mitochondrial dysfunction, inflammation, and cardiomyocyte pyroptosis, leading to improved left ventricular (LV) function. Methods: Wistar rats were divided into 5 groups, including i) control (0.9%NSS), ii) TRZ+VEH (TRZ, 4 mg/kg+VEH), iii) TRZ+α7 nicotinic AChR agonist (α7nAChR: PNU-282987, 3 mg/kg/day), iv) TRZ+muscarinic AChR agonist (mAChR: bethanechol, 12 mg/kg/day), and v) combined PNU+BET treatment groups (COM). At the end of the experiments, cardiac biochemical and functional analyses were determined. Results: TRZ-treated rats showed a decreased %LV ejection fraction (%LVEF) (Fig. 1A). Moreover, mitochondrial reactive oxygen species (ROS) levels and mitochondrial depolarization were increased in TIC rats (Fig. 1B-C). TRZ-treated rats also exhibited the upregulation of interleukin-6 mRNA, NLR family pyrin domain containing, and cleaved-gasdermin D/gasdermin expression (Fig. 1D-F). All AChR agonists similarly protected the hearts by attenuating cardiac mitochondrial dysfunctions, inflammation, and pyroptosis, leading to improved LV function in TIC rats (Fig. 1A-F). Conclusions: Either α7nAChR or mAChR agonist equally exerted cardioprotective effects against TIC by reducing cardiac mitochondrial dysfunction, inflammation, and pyroptosis, culminating in improved LV function. These findings provide potential novel treatment strategies against TIC.