Clinical Research
Radiation Injury
Sustained Inflammation Due to Nuclear Factor-Kappa B Activation in Irradiated Human Arteries

https://doi.org/10.1016/j.jacc.2009.10.047Get rights and content
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Objectives

The aim of this study was to investigate gene expression networks related to cardiovascular disease in radiated human arteries.

Background

Recent epidemiological studies have shown that radiotherapy is associated with cardiovascular disease years after treatment. However, the molecular mechanisms underlying late effects of radiation are poorly described.

Methods

Arterial biopsies from radiated and nonradiated human conduit arteries, from the same patient, were simultaneously harvested during microvascular free tissue transfer for cancer-reconstruction in 13 patients, 4 to 500 weeks from radiation treatment. Radiated and nonradiated arteries were compared, with Affymetrix (Santa Clara, California) microarrays on a subset of the material to generate candidate genes. A Taqman (Applied Biosystems, Foster City, California) low-density array of 45 selected genes was designed for analysis of the whole material.

Results

Thirteen genes were synchronously expressed in all patients (p = 0.0015), including CCL8, CCL3, CXCL2, DUSP5, FGFR2, HMOX1, HOXA9, IL-6, MMP-1, PTX3, RDH10, SOD2, and TNFAIP3. A majority of differentially regulated genes related to the nuclear factor-kappa B (NF-κB) signaling pathway and were dysregulated even years after radiation. The NF-κB activation was confirmed by immunohistochemistry and immunofluorescence.

Conclusions

In the present study, we found sustained inflammation due to NF-κB activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-κB. We also suggest that HOXA9 might be involved in the regulation of NF-κB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation.

Key Words

gene expression
human arteries
inflammation
irradiation

Abbreviations and Acronyms

cDNA
complementary deoxyribonucleic acid
IL
interleukin
MMP
matrix metalloproteinase
NF-κB
nuclear factor-kappa B
PBS
phosphate-buffered saline
RNA
ribonucleic acid
TLDA
Taqman low-density array
Tris
tris(hydroxymethyl)aminomethane

Cited by (0)

This study was supported by the Swedish Heart-Lung Foundation.