title: Irradiation of existing atherosclerotic lesions increased inflammation by favoring pro-inflammatory macrophages.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Gabriels
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, The Netherlands.
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.affiliation: 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.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Pol
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: te Poele
authors.affiliation: Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Department of Pathology, Academic Medical Center, The Netherlands.
authors.forename: Mat J
authors.initials: MJ
authors.lastname: Daemen
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, The Netherlands.
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stewart
authors.affiliation: Division of Experimental Vascular Pathology, Department of Pathology, Cardiovascular Research Institute Maastricht, The Netherlands. Electronic address: s.heeneman@maastrichtuniversity.nl.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000528:radiation effects; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000473:pathology*; D018450:Disease Progression; D007249:Inflammation / Q000209:etiology*; D008264:Macrophages / Q000502:physiology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E
keywords: Atherosclerosis; Macrophages; Radiotherapy