Stairley Rebecca A, Trouten Allison M, Li Shuang, Roddy Patrick L, DeLeon-Pennell Kristine Y, Lee Kyu-Ho, Sucov Henry M, Liu Chun, Tao Ge
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Antioxidants (Basel). 2024 Jun 26;13(7):769. doi: 10.3390/antiox13070769.
Mammalian cardiomyocytes have limited regenerative ability. Cardiac disease, such as congenital heart disease and myocardial infarction, causes an initial loss of cardiomyocytes through regulated cell death (RCD). Understanding the mechanisms that govern RCD in the injured myocardium is crucial for developing therapeutics to promote heart regeneration. We previously reported that ferroptosis, a non-apoptotic and iron-dependent form of RCD, is the main contributor to cardiomyocyte death in the injured heart. To investigate the mechanisms underlying the preference for ferroptosis in cardiomyocytes, we examined the effects of anti-ferroptotic reagents in infarcted mouse hearts. The results revealed that the anti-ferroptotic reagent did not improve neonatal heart regeneration, and further compromised the cardiac function of juvenile hearts. On the other hand, ferroptotic cardiomyocytes played a supportive role during wound healing by releasing pro-angiogenic factors. The inhibition of ferroptosis in the regenerating mouse heart altered the immune and angiogenic responses. Our study provides insights into the preference for ferroptosis over other types of RCD in stressed cardiomyocytes, and guidance for designing anti-cell-death therapies for treating heart disease.
哺乳动物心肌细胞的再生能力有限。诸如先天性心脏病和心肌梗死等心脏疾病，会通过程序性细胞死亡（RCD）导致心肌细胞最初的损失。了解受损心肌中调控RCD的机制对于开发促进心脏再生的治疗方法至关重要。我们之前报道过，铁死亡是一种非凋亡性且依赖铁的RCD形式，是受损心脏中心肌细胞死亡的主要原因。为了研究心肌细胞中铁死亡偏好的潜在机制，我们检测了抗铁死亡试剂对梗死小鼠心脏的影响。结果显示，抗铁死亡试剂并未改善新生心脏的再生，反而进一步损害了幼龄心脏的心脏功能。另一方面，铁死亡的心肌细胞通过释放促血管生成因子在伤口愈合过程中发挥支持作用。再生小鼠心脏中铁死亡的抑制改变了免疫和血管生成反应。我们的研究为应激心肌细胞中铁死亡相对于其他类型RCD的偏好提供了见解，并为设计治疗心脏病的抗细胞死亡疗法提供了指导。
