Karen Gabriels1, Saske Hoving2, Marion J Gijbels3, Jeffrey F Pol1, Johannes A te Poele2, Erik A Biessen1, Mat J Daemen4, Fiona A Stewart2, Sylvia Heeneman5. 1. Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands. 2. Division of Biological Stress Response, The Netherlands Cancer Institute, The Netherlands. 3. Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands; Department of Molecular Genetics, Maastricht University, Cardiovascular Research Institute Maastricht, The Netherlands; Department of Medical Biochemistry, Academic Medical Center, The Netherlands. 4. Department of Pathology, Academic Medical Center, The Netherlands. 5. Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands. Electronic address: s.heeneman@maastrichtuniversity.nl.
Abstract
BACKGROUND AND PURPOSE: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE(-/-) mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. MATERIAL AND METHODS: ApoE(-/-) mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham-treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. RESULTS: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. CONCLUSIONS: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque.
BACKGROUND AND PURPOSE: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancerpatients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE(-/-) mice. However, as older cancerpatients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. MATERIAL AND METHODS:ApoE(-/-) mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham-treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. RESULTS: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. CONCLUSIONS: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque.
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