College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, China.
J Cell Mol Med. 2020 Apr;24(7):4036-4050. doi: 10.1111/jcmm.15041. Epub 2020 Feb 19.
Higenamine (HG) is a natural benzylisoquinoline alkaloid isolated from Aconitum with positive inotropic and chronotropic effects. This study aimed to investigate the possible cardioprotective effects of HG combined with [6]-gingerol (HG/[6]-GR) against DOX-induced chronic heart failure (CHF) by comprehensive approaches. DOX-induced cardiotoxicity model in rats and H9c2 cells was established. Therapeutic effects of HG/[6]-GR on haemodynamics, serum indices and histopathology of cardiac tissue were analysed. Cell mitochondrial energy phenotype and cell mitochondrial fuel flex were measured by a Seahorse XFp analyser. Moreover, UHPLC-Q-TOF/MS was performed to explore the potential metabolites affecting the therapeutic effects and pathological process of CHF. To further investigate the potential mechanism of HG/[6]-GR, mRNA and protein expression levels of RAAS and LKB1/AMPK/Sirt1-related pathways were detected. The present data demonstrated that the therapeutic effects of HG/[6]-GR combination on CHF were presented in ameliorating heart function, down-regulation serum indices and alleviating histological damage of heart tissue. Besides, HG/[6]-GR has an effect on increasing cell viability of H9c2 cells, ameliorating DOX-induced mitochondrial dysfunction and elevating mitochondrial OCR and ECAR value. Metabolomics analyses showed that the therapeutic effect of HG/[6]-GR combination is mainly associated with the regulation of fatty acid metabolites and energy metabolism pathways. Furthermore, HG/[6]-GR has an effect on down-regulating RAAS pathway-related molecules and up-regulating LKB1/AMPKα/Sirt1-related pathway. The present work demonstrates that HG/[6]-GR prevented DOX-induced cardiotoxicity via the cardiotonic effect and promoting myocardial energy metabolism through the LKB1/AMPKα/Sirt1 signalling pathway, which promotes mitochondrial energy metabolism and protects against CHF.
盐酸育亨宾（HG）是一种从乌头属植物中分离得到的天然苄基异喹啉生物碱，具有正性肌力和变时作用。本研究旨在通过综合方法探讨 HG 与[6]-姜烯酚（HG/[6]-GR）联合应用对 DOX 诱导的慢性心力衰竭（CHF）的可能心脏保护作用。建立 DOX 诱导的大鼠心肌毒性模型和 H9c2 细胞模型，分析 HG/[6]-GR 对血流动力学、血清指标和心肌组织病理学的治疗作用。利用 Seahorse XFp 分析仪测定细胞线粒体能量表型和细胞线粒体燃料灵活性。此外，采用 UHPLC-Q-TOF/MS 探索影响 CHF 治疗效果和病理过程的潜在代谢物。为了进一步探讨 HG/[6]-GR 的潜在机制，检测了 RAAS 和 LKB1/AMPK/Sirt1 相关通路的 mRNA 和蛋白表达水平。本研究数据表明，HG/[6]-GR 联合治疗 CHF 的疗效表现在改善心功能、下调血清指标和减轻心肌组织病理损伤。此外，HG/[6]-GR 对 H9c2 细胞活力有一定的提高作用，可改善 DOX 诱导的线粒体功能障碍，提高线粒体 OCR 和 ECAR 值。代谢组学分析表明，HG/[6]-GR 联合治疗的疗效主要与脂肪酸代谢物和能量代谢途径的调节有关。此外，HG/[6]-GR 还可下调 RAAS 通路相关分子，上调 LKB1/AMPKα/Sirt1 相关通路。本研究表明，HG/[6]-GR 通过正性肌力作用和促进心肌能量代谢来预防 DOX 诱导的心脏毒性，通过 LKB1/AMPKα/Sirt1 信号通路促进线粒体能量代谢，从而保护 CHF。
