Mohr Mary E, Li Shuang, Trouten Allison M, Stairley Rebecca A, Roddy Patrick L, Liu Chun, Zhang Min, Sucov Henry M, Tao Ge
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
These authors contributed equally.
bioRxiv. 2023 Feb 8:2023.02.07.527364. doi: 10.1101/2023.02.07.527364.
Neonatal mouse hearts have transient renewal capacity which is lost in juvenile and adult hearts. After myocardial infarction (MI) in neonatal hearts, an initial loss of cardiomyocytes occurs but it is unclear through which type of regulated cell death (RCD). In the current studies, we induced MI in neonatal and juvenile mouse hearts, and show that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrate that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine factors and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. Meanwhile, the fibrogenic role of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.
新生小鼠心脏具有短暂的更新能力，而这种能力在幼年和成年心脏中会丧失。在新生心脏发生心肌梗死（MI）后，会出现心肌细胞的初始丧失，但尚不清楚是通过哪种类型的程序性细胞死亡（RCD）。在当前的研究中，我们在新生和幼年小鼠心脏中诱导MI，并表明缺血心肌细胞主要经历铁死亡，这是一种非凋亡且依赖铁的RCD形式。我们证明心脏成纤维细胞（CFs）通过旁分泌因子和直接的细胞间相互作用保护心肌细胞免受铁死亡。由于铁蛋白高表达，CFs对铁死亡表现出强大的抗性。同时，通常被认为对心脏功能有害的CFs的纤维化作用受到心肌细胞中配对样同源结构域2（Pitx2）信号通路的负调控。此外，Pitx2通过调节铁死亡基因来防止心肌细胞发生铁死亡。了解心肌细胞存活和死亡的调控机制可以确定针对MI的潜在可转化治疗策略。
