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CLINICAL RESEARCH: RADIATION INJURY

Sustained Inflammation Due to Nuclear Factor-Kappa B Activation in Irradiated Human Arteries

Martin Halle, MD, PhD^_*,,_*, Anders Gabrielsen, MD, PhD^,, Gabrielle Paulsson-Berne, PhD, Caroline Gahm, MD, PhD, Hanna E. Agardh, BA, Filip Farnebo, MD, PhD^_* and Per Tornvall, MD, PhD^,

^_* Department of Molecular Medicine and Surgery, Section of Reconstructive Plastic Surgery, Karolinska Institute, Stockholm, Sweden
Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
Department of Medicine, Section of Cardiology, Karolinska Institute, Stockholm, Sweden
Department of ORL, Head and Neck Surgery, Karolinska Institute, Stockholm, Sweden

Manuscript received June 28, 2009; revised manuscript received September 22, 2009, accepted October 27, 2009.

^_* Reprint requests and correspondence: Dr. Martin Halle, Reconstructive Plastic Surgery, Karolinska University Hospital, 171 76 Stockholm, Sweden (Email: martin.halle{at}ki.se).

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-B) signaling pathway and were dysregulated even years after radiation. The NF-B activation was confirmed by immunohistochemistry and immunofluorescence.

Conclusions: In the present study, we found sustained inflammation due to NF-B activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-B. We also suggest that HOXA9 might be involved in the regulation of NF-B 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-B = nuclear factor-kappa B   PBS = phosphate-buffered saline   RNA = ribonucleic acid   TLDA = Taqman low-density array   Tris = tris(hydroxymethyl)aminomethane

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