Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
J Cardiovasc Pharmacol. 2023 Aug 1;82(2):104-116. doi: 10.1097/FJC.0000000000001434.
Studies have demonstrated the roles of trimetazidine beyond being an antianginal agent in ischemic heart disease (IHD) treatment associated with mechanisms of calcium regulation. Our recent studies revealed that mitochondrial calcium uniporter (MCU, the pore-forming unit responsible for mitochondrial calcium entrance) inhibition provided cardioprotective effects for failing hearts. Because trimetazidine and MCU are associated with calcium homeostasis, we hypothesized that trimetazidine may affect MCU to restore the failing heart function. In the present study, we tested this hypothesis in the context of cardiac ischemia in vivo and in vitro. The IHD model was established in male C57BL/6 mice followed by trimetazidine administration intraperitoneally at 20 mg/kg q.o.d for 8 weeks. In vitro studies were performed in a hypoxia model using primary rat neonate cardiomyocytes. The mice survival outcomes and heart function, pathohistologic, and biological changes were analyzed. The results demonstrated that trimetazidine treatment resulted in longer life spans and heart function improvement accompanied by restoration of mitochondrial calcium levels and increase in ATP production via MCU down-regulation. Studies in vitro further showed that trimetazidine treatment and MCU inhibition decreased reactive oxygen species (ROS) production, inhibited the NFκB pathway, and protected the cardiomyocytes from hypoxic injury, and vice versa. Thus, the present study unveils a unique mechanism in which trimetazidine is involved in ameliorating the ischemic failing heart via MCU down-regulation and the following mitochondrial calcium homeostasis restoration, ROS reduction, and cardiomyocyte protection through NFκB pathway inhibition. This mechanism provides a novel explanation for the treatment effects of trimetazidine on IHD.
研究表明，曲美他嗪在缺血性心脏病（IHD）治疗中除了作为抗心绞痛药物外，还与钙调节机制有关。我们最近的研究表明，线粒体钙单向转运体（MCU，负责线粒体钙进入的孔形成单位）抑制为衰竭心脏提供了心脏保护作用。由于曲美他嗪和 MCU 与钙稳态有关，我们假设曲美他嗪可能通过影响 MCU 来恢复衰竭心脏的功能。在本研究中，我们在体内和体外心脏缺血的背景下测试了这一假设。在雄性 C57BL/6 小鼠中建立 IHD 模型，然后腹膜内给予曲美他嗪 20mg/kg，每天一次，连续 8 周。体外研究在原代大鼠乳鼠缺氧模型中进行。分析了小鼠的生存结果和心脏功能、病理组织学和生物学变化。结果表明，曲美他嗪治疗可延长寿命并改善心脏功能，同时恢复线粒体钙水平并通过下调 MCU 增加 ATP 产生。体外研究进一步表明，曲美他嗪治疗和 MCU 抑制可减少活性氧（ROS）的产生，抑制 NFκB 途径，并保护心肌细胞免受缺氧损伤，反之亦然。因此，本研究揭示了一种独特的机制，即曲美他嗪通过下调 MCU 并随后恢复线粒体钙稳态、减少 ROS 和抑制 NFκB 途径来改善缺血性衰竭心脏，从而为曲美他嗪治疗 IHD 的作用机制提供了新的解释。
