藜芦碱通过 NLRP3/Caspase-1/IL-1β 信号通路发挥慢性心力衰竭的抗心律失常作用。
Celastrol exerts antiarrhythmic effects in chronic heart failure via NLRP3/Caspase-1/IL-1β signaling pathway.
机构信息
Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, PR China; Cardiac Autonomic Nervous System Research Center of Wuhan University, PR China; Taikang Center for Life and Medical Sciences, Wuhan University, PR China; Hubei Key Laboratory of Autonomic Nervous System Modulation, PR China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, PR China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China.
Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, PR China; Cardiac Autonomic Nervous System Research Center of Wuhan University, PR China; Taikang Center for Life and Medical Sciences, Wuhan University, PR China; Hubei Key Laboratory of Autonomic Nervous System Modulation, PR China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, PR China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China.
出版信息
Biomed Pharmacother. 2024 Aug;177:117121. doi: 10.1016/j.biopha.2024.117121. Epub 2024 Jul 14.
OBJECTIVES
Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI.
METHODS
Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24 hours. Nigericin was used to activate the NLRP3 inflammasome.
RESULTS
Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway.
CONCLUSIONS
Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1β pathway.
目的
雷公藤红素在各种病理情况下具有广泛的治疗应用，包括慢性炎症。先前的研究表明雷公藤红素具有强大的心脏保护作用。然而，其在减少心肌梗死后室性心律失常（VA）方面的潜力尚未得到充分关注。因此，本研究旨在阐明雷公藤红素对心肌梗死后大鼠 VA 和心脏电生理参数的调节作用的潜在机制。
方法
将 Sprague-Dawley 大鼠随机分为假手术组、心肌梗死组和心肌梗死+雷公藤红素组。在 MI 和 MI+Cel 组中，结扎左冠状动脉。进行心电图、心率变异性（HRV）、心室电生理参数分析、心室组织学染色、酶联免疫吸附测定（ELISA）、Western blot 和实时定量聚合酶链反应（qRT-PCR），以阐明雷公藤红素的潜在机制。此外，将 H9c2 细胞置于缺氧条件下，建立心肌梗死体外模型，然后用雷公藤红素处理 24 小时。用 Nigericin 激活 NLRP3 炎性小体。
结果
与 MI 组相比，MI+celastrol 组心脏电生理不稳定明显减轻。此外，雷公藤红素改善 HRV，上调 Cx43、Kv.4.2、Kv4.3 和 Cav1.2 水平，减轻心肌纤维化，抑制 NLRP3 炎性小体途径。体外条件也支持雷公藤红素对 NLRP3 炎性小体途径的调节作用。
结论
雷公藤红素可能通过促进自主神经重塑、心室电重构和离子通道重塑，部分缓解 MI 后 VA 的不良影响，并通过抑制 NLRP3/Caspase-1/IL-1β途径部分缓解心室纤维化和炎症反应，从而减轻 MI 后 VA 的不良影响。
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