Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Bioelectricity Laboratory, Department of Pharmacology, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.
FASEB J. 2023 Jul;37(7):e22999. doi: 10.1096/fj.202300253R.
Sudden cardiac death (SCD) remains a major cause of global mortality. In addition to modern interventions, botanical folk medicines have long been used to treat cardiovascular disease, although the efficacy and underlying mechanisms are often unresolved. Aloperine, a bioactive quinolizidine alkaloid isolated from Sophora alopecuroides plants, exhibits antioxidant, anti-inflammatory, antitumor, and vasorelaxant properties, but possible antiarrhythmic effects of aloperine in SCD are unclear. Here, we examined whether aloperine protects against ischemia and reperfusion injury-associated lethal ventricular arrhythmia and sudden cardiac death. Rats were divided into sham, control, and aloperine groups, and reperfusion-provoked ventricular arrhythmogenesis, cardiac damage markers, and signaling pathways quantified following left main coronary artery ischemia and reperfusion. In vitro studies of effects of aloperine on hERG and Kv4.3 cardiac voltage-gated potassium (Kv) channels were performed using two-electrode voltage clamp analysis of cloned channels expressed in Xenopus laevis oocytes. Aloperine pretreatment (10 mg/kg) did not affect baseline cardiac electrical stability; yet, it reduced ventricular arrhythmogenesis and susceptibility to SCD (mortality rate: control: 64.3%; aloperine: 0%) induced by reperfusion injury. Aloperine also reduced serum levels of LDH, CK-MB, α-HBDH, and cTnI post-I/R, and stimulated phosphorylation of ventricular ERK1/2 and STAT-3, which are key components of RISK and SAFE signaling pathways. Inhibition of either ERK1/2 (with U0126) or STAT-3 (with Ag490) abolished aloperine-induced anti-arrhythmic effects and ERK1/2 and STAT-3 phosphorylation. Interestingly, while aloperine (100 μM) had no effect on cloned Kv4.3 activity, aloperine (1 μM and up) negative-shifted the voltage dependence of hERG activation by ~10 mV and increased peak hERG current by 35%. Thus, aloperine exerts striking anti-arrhythmic effects against myocardial ischemia and reperfusion injury-induced severe lethal ventricular arrhythmia and sudden cardiac death via the ERK1/2/STAT-3 signaling pathway, with potential additional contribution from increased cardiac myocyte repolarization capacity via augmented hERG activity.
心源性猝死（SCD）仍然是全球死亡率的主要原因。除了现代干预措施外，植物民间药物长期以来一直用于治疗心血管疾病，尽管疗效和潜在机制往往仍未得到解决。从苦参植物中分离得到的生物活性喹诺里嗪生物碱阿罗品具有抗氧化、抗炎、抗肿瘤和血管舒张作用，但阿罗品对 SCD 的可能抗心律失常作用尚不清楚。在这里，我们研究了阿罗品是否能预防缺血再灌注损伤相关的致命性室性心律失常和心源性猝死。将大鼠分为假手术组、对照组和阿罗品组，并在左主干冠状动脉缺血再灌注后定量检测再灌注引起的室性心律失常发生、心脏损伤标志物和信号通路。使用双电极电压钳分析在非洲爪蟾卵母细胞中表达的克隆通道，进行阿罗品对 hERG 和 Kv4.3 心脏电压门控钾 (Kv) 通道的体外研究。阿罗品预处理（10mg/kg）不影响基线心脏电稳定性；然而，它减少了再灌注损伤引起的室性心律失常发生和 SCD 易感性（死亡率：对照组：64.3%；阿罗品组：0%）。阿罗品还降低了再灌注后血清中的 LDH、CK-MB、α-HBDH 和 cTnI 水平，并刺激了心室 ERK1/2 和 STAT-3 的磷酸化，这是 RISK 和 SAFE 信号通路的关键组成部分。ERK1/2（用 U0126 抑制）或 STAT-3（用 Ag490 抑制）的抑制消除了阿罗品诱导的抗心律失常作用和 ERK1/2 和 STAT-3 的磷酸化。有趣的是，虽然阿罗品（100μM）对克隆 Kv4.3 活性没有影响，但阿罗品（1μM 及以上）将 hERG 激活的电压依赖性负移约 10mV，并将 hERG 峰值电流增加 35%。因此，阿罗品通过 ERK1/2/STAT-3 信号通路对心肌缺血再灌注损伤引起的严重致命性室性心律失常和心源性猝死产生显著的抗心律失常作用，通过增加 hERG 活性增强心肌细胞复极能力可能有额外贡献。
