Multi-omic Analysis of Non-human Primate Heart after Partial-body Radiation with Minimal Bone Marrow Sparing

Abstract

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.

Role of cellular retinol‐binding protein, type 1 and retinoid homeostasis in the adult mouse heart: A multi‐omic approach

“…Metabolites are limited to those contained in the Biocrates AbsoluteIDQ p180 kit, which is a subset of the whole metabolomic profile. The Biocrates kit has only been validated for plasma, but it has been previously used by us and by other groups for analyzing heart tissue 98–101 . Hearts were not perfused upon collection consistent with other studies in the literature using the Biocrates kit for analysis of heart tissue, 98–100 however it is possible blood contained within the tissue contributes signal towards the total protein and metabolite content.…”

“…The Biocrates kit has only been validated for plasma, but it has been previously used by us and by other groups for analyzing heart tissue. [98][99][100][101] Hearts were not perfused upon collection consistent with other studies in the literature using the Biocrates kit for analysis of heart tissue, [98][99][100] however it is possible blood contained within the tissue contributes signal towards the total protein and metabolite content. Samples were limited to availability of animals at the time, and future studies would be necessary to inform on any metabolomic and/or proteomic gender or age differences in Rbp1 −/− mice.…”

Preclinical models of radiation-induced cardiac toxicity: Potential mechanisms and biomarkers

“…Manifestations of RIHD are significantly common between pigs and non-human primates with humans ( 65 – 67 ) but these species have also been used by only a few groups as they carry significantly higher costs than other models ( 19 – 21 , 71 ).…”

Animal Models: A Non-human Primate and Rodent Animal Model Research Platform, Natural History, and Biomarkers to Predict Clinical Outcome

“…A systems biology approach allows for an unbiased assessment of the natural history of acute and delayed effects of radiation injury on the molecular level. Thorough analyses of NHP PBI/BM-sparing models using omics-based methods has provided a more complete understanding of natural history on the molecular level defining quantifiable molecules with biomarker potential (Jones et al 2015a; Carter et al 2019; Huang et al 2020a and b, 2021a and b; Kumar et al 2020, 2021; Muller et al 2021; Yu et al 2021; Zalesak-Kravec et al 2021). Similar approaches in other NHP exposure models (whole thorax lung irradiation, TBI) (Carter et al 2015, 2017; Jones et al 2015a) as well as mouse models (Jones et al 2015b, 2017a, 2019a and b; Huang et al 2019a and b) are useful toward providing additional evidentiary support for biomarker utility.…”