Abstract
The cardiovascular biology of proton radiotherapy is not well understood. We aimed to compare the genomic dose-response to proton and gamma radiation of the mouse aorta to assess whether their vascular effects may diverge. We performed comparative RNA sequencing of the aorta following (4 hrs) total-body proton and gamma irradiation (0.5–200 cGy whole body dose, 10 dose levels) of conscious mice. A trend analysis identified genes that showed a dose response. While fewer genes were dose-responsive to proton than gamma radiation (29 vs. 194 genes; q-value ≤ 0.1), the magnitude of the effect was greater. Highly responsive genes were enriched for radiation response pathways (DNA damage, apoptosis, cellular stress and inflammation; p-value ≤ 0.01). Gamma, but not proton radiation induced additionally genes in vasculature specific pathways. Genes responsive to both radiation types showed almost perfectly superimposable dose-response relationships. Despite the activation of canonical radiation response pathways by both radiation types, we detected marked differences in the genomic response of the murine aorta. Models of cardiovascular risk based on photon radiation may not accurately predict the risk associated with proton radiation.
Highlights
Radiotherapy is a widely used cancer treatment resulting in the exposure to ionizing radiation of nearly half a million Americans every year
Narrow distributions of Δ expression rank indicate that the impact on gene expression of a physical dose is similar between radiation types
Trend analysis across the 10 doses revealed that fewer genes increased dose-dependently in response to proton radiation than gamma radiation (Table 1)
Summary
Radiotherapy is a widely used cancer treatment resulting in the exposure to ionizing radiation of nearly half a million Americans every year. Therapeutic gamma irradiation that includes the heart and aortic arch in the radiation field is associated with increases in the rates of myocardial infarction, congestive heart failure, valve disease and arrhythmia [1,2,3]. These complications may have long latency times but continue to rise over decades after the initial treatment [4,5,6] in a radiation dose-dependent fashion [7,8,9].
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