Martin Halle1, Anders Gabrielsen2, Gabrielle Paulsson-Berne3, Caroline Gahm4, Hanna E Agardh3, Filip Farnebo5, Per Tornvall2. 1. 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. Electronic address: martin.halle@ki.se. 2. Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Department of Medicine, Section of Cardiology, Karolinska Institute, Stockholm, Sweden. 3. Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden. 4. Department of ORL, Head and Neck Surgery, Karolinska Institute, Stockholm, Sweden. 5. Department of Molecular Medicine and Surgery, Section of Reconstructive Plastic Surgery, Karolinska Institute, Stockholm, Sweden.
Abstract
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-kappaB) signaling pathway and were dysregulated even years after radiation. The NF-kappaB activation was confirmed by immunohistochemistry and immunofluorescence. CONCLUSIONS: In the present study, we found sustained inflammation due to NF-kappaB activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-kappaB. We also suggest that HOXA9 might be involved in the regulation of NF-kappaB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
OBJECTIVES: The aim of this study was to investigate gene expression networks related to cardiovascular disease in radiatedhuman 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-kappaB) signaling pathway and were dysregulated even years after radiation. The NF-kappaB activation was confirmed by immunohistochemistry and immunofluorescence. CONCLUSIONS: In the present study, we found sustained inflammation due to NF-kappaB activation in humanradiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-kappaB. We also suggest that HOXA9 might be involved in the regulation of NF-kappaB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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