Cardiomyocyte-fibroblast interaction regulates ferroptosis and fibrosis after myocardial injury

• DOI: 10.1016/j.isci.2024.109219
• Publication Date: 2024-02-15T10:51:59Z
• Authors: Mary E. Mohr; Shuang Li; Allison M. Trouten; Rebecca A. Stairley; Patrick L. Roddy; Chun Liu; Min Zhang; Henry M. Sucov; Ge Tao
• Keywords: 0301 basic medicine; 03 medical and health sciences; cardiovascular medicine; Physiology; Science; cell biology; Q; Article

SUMMARYNeonatal 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.