College of Life Science, Anhui Medical University, Hefei, People's Republic of China.
Department of Experimental Haematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
Am J Physiol Cell Physiol. 2023 Jun 1;324(6):C1320-C1331. doi: 10.1152/ajpcell.00466.2022. Epub 2023 May 8.
Radiation-induced heart disease (RIHD) progresses over time and may manifest decades after the initial radiation exposure, which is associated with significant morbidity and mortality. The clinical benefit of radiotherapy is always counterbalanced by an increased risk of cardiovascular events in survivors. There is an urgent need to explore the effect and the underlying mechanism of radiation-induced heart injury. Mitochondrial damage widely occurs in irradiation-induced injury, and mitochondrial dysfunction contributes to necroptosis development. Experiments were performed using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and rat H9C2 cells to investigate the effect of mitochondrial injury on necroptosis in irradiated cardiomyocytes and to further elucidate the mechanism underlying radiation-induced heart disease and discover possible preventive targets. After γ-ray irradiation, the expression levels of necroptosis markers were increased, along with higher oxidative stress and mitochondrial injury. These effects could be abated by overexpression of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1). Inhibiting oxidative stress or increasing the expression of PTPMT1 could protect against radiation-induced mitochondrial injury and then decrease the necroptosis of cardiomyocytes. These results suggest that PTPMT1 may be a new target for the treatment of radiation-induced heart disease. Effective strategies are still lacking for treating RIHD, with unclear pathological mechanisms. In cardiomyocytes model of radiation-induced injuries, we found γ-ray irradiation decreased the expression of PTPMT1, increased oxidative stress, and induced mitochondrial dysfunction and necroptosis in iPSC-CMs. ROS inhibition attenuated radiation-induced mitochondrial damage and necroptosis. PTPMT1 protected cardiomyocytes from necroptosis induced by γ-ray irradiation by alleviating mitochondrial injury. Therefore, PTPMT1 might be a potential strategy for treating RIHD.
放射性心脏病（RIHD）是一种进行性疾病，在初始辐射暴露后可能会在数十年后显现，这与重大发病率和死亡率相关。放射治疗的临床获益总是与幸存者心血管事件风险增加相平衡。迫切需要探索放射性心脏损伤的作用和潜在机制。线粒体损伤广泛发生于辐射诱导的损伤中，线粒体功能障碍导致坏死性凋亡的发展。使用诱导多能干细胞衍生的心肌细胞（iPSC-CMs）和大鼠 H9C2 细胞进行实验，以研究线粒体损伤对辐照心肌细胞坏死性凋亡的影响，并进一步阐明放射性心脏病的发病机制，发现可能的预防靶点。γ射线照射后，坏死性凋亡标志物的表达水平增加，同时伴有更高的氧化应激和线粒体损伤。过表达蛋白酪氨酸磷酸酶 1（PTPMT1）可以减轻这些效应。抑制氧化应激或增加 PTPMT1 的表达可以防止辐射诱导的线粒体损伤，从而减少心肌细胞的坏死性凋亡。这些结果表明，PTPMT1 可能是治疗放射性心脏病的新靶点。目前针对 RIHD 的治疗方法仍然缺乏有效策略，其病理机制尚不清楚。在辐射诱导损伤的心肌细胞模型中，我们发现γ射线照射降低了 PTPMT1 的表达，增加了氧化应激，诱导了 iPSC-CMs 中的线粒体功能障碍和坏死性凋亡。ROS 抑制减轻了辐射诱导的线粒体损伤和坏死性凋亡。PTPMT1 通过减轻线粒体损伤来保护心肌细胞免受γ射线照射诱导的坏死性凋亡。因此，PTPMT1 可能是治疗 RIHD 的一种潜在策略。
