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.
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
iScience. 2024 Feb 15;27(3):109219. doi: 10.1016/j.isci.2024.109219. eCollection 2024 Mar 15.
Neonatal mouse hearts have transient renewal capacity, which is lost in juvenile and adult stages. In neonatal mouse hearts, myocardial infarction (MI) causes an initial loss of cardiomyocytes. However, it is unclear which type of regulated cell death (RCD) occurs in stressed cardiomyocytes. In the current studies, we induced MI in neonatal and juvenile mouse hearts and showed that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrated that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine effects and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. The fibrogenic activity 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，这种能力在幼年和成年阶段会丧失。在新生小鼠心脏中，心肌梗死（MI）会导致心肌细胞最初的损失。然而，尚不清楚在应激的心肌细胞中发生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了MI，并表明缺血心肌细胞主要发生铁死亡，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）通过旁分泌作用和直接的细胞间相互作用保护心肌细胞免受铁死亡。由于铁蛋白表达高，CFs对铁死亡表现出很强的抗性。通常被认为对心脏功能有害的CFs的纤维化活性受到心肌细胞中配对样同源结构域2（Pitx2）信号的负调控。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。
