Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China.
Eur J Pharmacol. 2022 Apr 5;920:174799. doi: 10.1016/j.ejphar.2022.174799. Epub 2022 Feb 17.
High levels of circulating catecholamines are related to raise risk of cardiac arrhythmias. In addition, our recent studies have suggested that pinocembrin could decrease the susceptibility to arrhythmias in several rat models, including chronic ischemic heart failure, myocardial infarction and depression. In this research, the effects of pinocembrin on ventricular fibrillation (VF) susceptibility were investigated in rats treated with isoproterenol (ISO) and further explored the possible mechanism.
Cardiac remodeling was induced by intraperitoneally injection ISO (5 mg/kg) 7 days. Simultaneously, Rats were received pinocembrin (5 mg/kg) or saline by tail vein injection. The effects of pinocembrin were evaluated by electrocardiogram parameters, ventricular electrophysiological parameters, echocardiographic, western blot, ventricular histology, biochemical examinations. In vitro, we cultured H9C2 cardiomyocytes to further define the mechanisms.
Compared with ISO group, pinocembrin remarkably decreased VF inducibility rate, attenuated the shortening of QT and corrected QT (QTc) interval, action potential duration (APD), ventricular effective refractory period (ERP), and increased the protein levels of Kv4.2 and Kv4.3 and Cav1.2 and decreased phosphorylated Ca calmodulin-dependent kinase Ⅱ (p-CaMK Ⅱ). Pinocembrin also alleviated ventricular fibrosis, hypertrophy and increased expression of connexin protein 43 (Cx43). In addition, pinocembrin markedly downregulated levels of malondialdehyde (MDA), hydrogen peroxide (HO), oxidized glutathione (GSSG) and increased the activity of superoxide dismutase (SOD) and glutathione (GSH) levels in circulation and cardiac tissue. Pinocembrin reduced the reactive oxygen species (ROS) levels. Furthermore, after treatment of pinocembrin the content of NADPH Oxidase-4 (NOX4) and NADPH Oxidase-2 (NOX2) was significantly lower and the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly higher. In vitro, we found that Nrf2 inhibitor remarkably reduced the antioxidant effects of pinocembrin, which further demonstrated that the effect of pinocembrin was related to activation of Nrf2.
Our data demonstrate that pinocembrin decreases ventricular electrical remodeling, ion remodeling, ventricular fibrosis, hypertrophy and suppresses isoproterenol-induced oxidative stress. The findings shown that pinocembrin mediates antiarrhythmic effects in rats with isoproterenol-induced cardiac remodeling related to Nrf2/HO-1 pathway.
循环儿茶酚胺水平升高与心律失常风险增加有关。此外，我们最近的研究表明，白杨素可降低几种大鼠模型（包括慢性缺血性心力衰竭、心肌梗死和抑郁症）中心律失常的易感性。在这项研究中，研究了白杨素对异丙肾上腺素（ISO）处理大鼠室颤（VF）易感性的影响，并进一步探讨了可能的机制。
通过腹腔注射 ISO（5mg/kg）7 天诱导心脏重塑。同时，通过尾静脉注射给予大鼠白杨素（5mg/kg）或生理盐水。通过心电图参数、心室电生理参数、超声心动图、western blot、心室组织学和生化检查评估白杨素的作用。在体外，我们培养 H9C2 心肌细胞以进一步确定机制。
与 ISO 组相比，白杨素可显著降低 VF 诱导率，减轻 QT 和校正 QT（QTc）间期、动作电位持续时间（APD）、心室有效不应期（ERP）缩短，并增加 Kv4.2 和 Kv4.3 以及 Cav1.2 的蛋白水平，降低磷酸化钙调蛋白依赖性激酶Ⅱ（p-CaMKⅡ）水平。白杨素还可减轻心室纤维化、肥大和连接蛋白 43（Cx43）表达增加。此外，白杨素可显著降低循环和心肌组织中丙二醛（MDA）、过氧化氢（HO）、氧化型谷胱甘肽（GSSG）水平，并增加超氧化物歧化酶（SOD）和谷胱甘肽（GSH）水平，降低活性氧（ROS）水平。此外，白杨素治疗后 NADPH 氧化酶-4（NOX4）和 NADPH 氧化酶-2（NOX2）含量显著降低，核因子红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）水平显著升高。体外研究发现，Nrf2 抑制剂显著降低了白杨素的抗氧化作用，进一步证实了白杨素的作用与 Nrf2 激活有关。
我们的数据表明，白杨素可降低心室电重构、离子重构、心室纤维化、肥大，并抑制异丙肾上腺素诱导的氧化应激。研究结果表明，白杨素通过 Nrf2/HO-1 通路介导异丙肾上腺素诱导的心脏重塑大鼠的抗心律失常作用。
