PDF(Pubmed)
Abstract：
Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.
摘要：
Ferroptosis是心肌缺血再灌注（I/R）损伤中至关重要的调节性细胞死亡过程。然而,心肌铁中毒的确切机制尚不清楚。在这项研究中,我们研究了甲基丙二酸（MMA）与I/R后心肌细胞铁凋亡活化相关的病理生理机制。我们发现在缺氧/复氧（H/R）条件下，再灌注后急性心肌损伤患者和AC16细胞的MMA水平升高。发现MMA治疗与心肌细胞过度氧化应激有关，导致铁凋亡相关的心肌损伤。在I/R损伤的小鼠中，MMA治疗加重心肌氧化应激和铁凋亡，放大了心肌梗塞的大小和心脏功能障碍。机械上,MMA促进NOX2/4表达以增加心肌细胞中活性氧（ROS）的产生，加重心肌损伤。值得注意的是,增加的ROS通过抑制溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的表达进一步激活了铁凋亡。此外,MMA通过增加核因子E2相关因子2（NRF2）与海带样ECH相关蛋白1（KEAP1）之间的相互作用来降低NRF2的异位核分布。这阻碍了NRF2下游的GPX4/SLC7A11的激活，激活了铁凋亡并加重了心肌细胞损伤。总的来说，我们的研究表明，MMA激活氧化应激和ROS的产生，在I/R模型中诱导铁死亡加剧心肌细胞损伤。这些发现可能为I/R损伤的临床治疗提供新的视角，值得进一步研究。
