Zhou Ji-Chao, Jin Cai-Cai, Wei Xiao-Li, Xu Rui-Bing, Wang Ruo-Yu, Zhang Zhi-Meng, Tang Bo, Yu Jin-Mei, Yu Jiao-Jiao, Shang Shuang, Lv Xiao-Xi, Hua Fang, Li Ping-Ping, Hu Zhuo-Wei, Shen Yong-Mei, Wang Feng-Peng, Ma Xiu-Ying, Cui Bing, Geng Fu-Neng, Zhang Xiao-Wei
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Sichuan Engineering Research Center for Medicinal Animals, Sichuan, China.
Front Pharmacol. 2023 Apr 12;14:1118017. doi: 10.3389/fphar.2023.1118017. eCollection 2023.
Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of , shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.
异常线粒体自噬已被确定为大多数心脏病理过程中能量代谢紊乱的驱动因素。然而，找到有效的靶向药物并揭示其精确的调节机制仍然是未被攻克的难题。附子，毛茛科植物乌头的子根，具有独特的回阳救逆功效，已在临床上广泛应用。中乌头碱作为附子的主要强心成分，已在多种心肌病模型中被证明有效。在此，我们旨在确定中乌头碱介导的梗阻性线粒体自噬恢复的一种前所未有的心脏保护机制。在阿霉素（DOX）诱导的心力衰竭模型中评估了中乌头碱的功能影响。DOX处理的小鼠表现出特征性的心脏功能障碍、异位心肌能量紊乱以及心肌细胞中线粒体自噬受损，而中乌头碱可显著逆转这些情况。中乌头碱的心脏保护作用主要归因于其促进心肌细胞中线粒体自噬恢复的能力，线粒体自噬诱导的关键介质PINK1表达升高证明了这一点。沉默或失活线粒体自噬可完全消除中乌头碱的保护作用。总之，我们的研究结果表明，中乌头碱的心脏保护作用似乎依赖于PINK1诱导的线粒体自噬的激活，并且中乌头碱可能构成一种有前途的治疗心力衰竭的药物。
