University of Maryland, School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD.
Medical Sciences Division, Northern Ontario School of Medicine, Sudbury, ON, Canada; Departments of Chemistry and Biochemistry, and Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON, Canada.
Health Phys. 2021 Oct 1;121(4):352-371. doi: 10.1097/HP.0000000000001478.
High-dose radiation exposure results in hematopoietic and gastrointestinal acute radiation syndromes followed by delayed effects of acute radiation exposure, which encompasses multiple organs, including heart, kidney, and lung. Here we sought to further characterize the natural history of radiation-induced heart injury via determination of differential protein and metabolite expression in the heart. We quantitatively profiled the proteome and metabolome of left and right ventricle from non-human primates following 12 Gy partial body irradiation with 2.5% bone marrow sparing over a time period of 3 wk. Global proteome profiling identified more than 2,200 unique proteins, with 220 and 286 in the left and right ventricles, respectively, showing significant responses across at least three time points compared to baseline levels. High-throughput targeted metabolomics analyzed a total of 229 metabolites and metabolite combinations, with 18 and 22 in the left and right ventricles, respectively, showing significant responses compared to baseline levels. Bioinformatic analysis performed on metabolomic and proteomic data revealed pathways related to inflammation, energy metabolism, and myocardial remodeling were dysregulated. Additionally, we observed dysregulation of the retinoid homeostasis pathway, including significant post-radiation decreases in retinoic acid, an active metabolite of vitamin A. Significant differences between left and right ventricles in the pathology of radiation-induced injury were identified. This multi-omic study characterizes the natural history and molecular mechanisms of radiation-induced heart injury in NHP exposed to PBI with minimal bone marrow sparing.
高剂量辐射暴露会导致造血和胃肠道急性辐射综合征，随后是急性辐射暴露的延迟效应，涉及多个器官，包括心脏、肾脏和肺。在这里，我们试图通过确定心脏中差异蛋白和代谢物的表达来进一步描述辐射诱导的心脏损伤的自然史。我们对接受 12Gy 局部全身照射（2.5%骨髓保留）的非人类灵长类动物的左、右心室进行了蛋白质组和代谢组的定量分析，时间跨度为 3 周。全局蛋白质组分析鉴定出超过 2200 种独特的蛋白质，其中左、右心室分别有 220 和 286 种蛋白质的表达水平在至少三个时间点与基线水平相比有显著变化。高通量靶向代谢组学分析了总共 229 种代谢物和代谢物组合，其中左、右心室分别有 18 和 22 种代谢物的表达水平与基线水平相比有显著变化。对代谢组学和蛋白质组学数据进行的生物信息学分析揭示了与炎症、能量代谢和心肌重构相关的途径失调。此外，我们观察到视黄醇稳态途径的失调，包括辐射后视黄酸（维生素 A 的活性代谢物）显著减少。还确定了在受 PBI 照射、最小骨髓保留的 NHP 中，辐射诱导损伤的左、右心室之间存在病理学差异。这项多组学研究描绘了 PBI 暴露的 NHP 中辐射诱导的心脏损伤的自然史和分子机制。
