title: Late inflammatory and thrombotic changes in irradiated hearts of C57BL/6 wild-type and atherosclerosis-prone ApoE-deficient mice.
abstract: OBJECTIVE
  Radiation-induced heart disease represents a late complication of thoracic radiotherapy. We investigated the inflammatory and thrombotic response after local heart irradiation in wild-type and atherosclerosis-prone mice.
  
  
  METHODS
  Atherosclerosis-prone ApoE(-/-) and C57BL/6 wild-type mice were sacrificed 20, 40, and 60 weeks after irradiation with 0.2, 2, 8, or 16 Gy. The expression of CD31, vascular cell adhesion molecule-1 (VCAM-1), thrombomodulin (TM), and CD45 were quantified by immunofluorescence staining of heart tissue sections.
  
  
  RESULTS
  Microvascular density decreased at 40 weeks after 16 Gy in C57BL/6 but not in ApoE(-/-) mice. CD31 expression declined in C57BL/6 mice at 40 weeks (8 Gy), but increased in ApoE(-/-) mice at 20 (2/8/16 Gy) and 60 weeks (16 Gy). Capillary area decreased in C57BL/6 at 40 weeks (8/16 Gy) but increased in ApoE(-/-) mice at 20 weeks (16 Gy). Endocardial VCAM-1 expression remained unchanged. TM-positive capillaries decreased at 40 weeks (8/16 Gy) in C57BL/6 and at 60 weeks (2/16 Gy) in ApoE(-/-) mice. Leukocyte infiltration transiently rose 40 weeks after 8 Gy (only ApoE(-/-)) and 16 Gy. After receiving a low irradiation dose of 0.2 Gy, no significant changes were observed in any of the mouse models.
  
  
  CONCLUSIONS
  This study demonstrated that local heart irradiation affects microvascular structure and induces inflammatory/thrombotic responses in mice in a dose- and time-dependent manner. Thereby, significant prothrombotic changes were found in both strains, although they were progressive in ApoE(-/-) mice only. Proinflammatory responses, like the increase of adhesion molecules and leukocyte infiltration, were more pronounced and occurred at lower doses in ApoE(-/-) vs. C57BL/6 mice. These findings indicate that metabolic risk factors, such as decreased ApoE lipoproteins, may lead to an enhanced proinflammatory and prothrombotic late response in locally irradiated hearts.
authors.affiliation: Department of Radiation Therapy, University of Leipzig, Stephanstrasse 9a, 04103, Leipzig, Germany, ina.patties@medizin.uni-leipzig.de.
authors.forename: I
authors.initials: I
authors.lastname: Patties
authors.forename: J
authors.initials: J
authors.lastname: Haagen
authors.forename: W
authors.initials: W
authors.lastname: Dörr
authors.forename: G
authors.initials: G
authors.lastname: Hildebrandt
authors.forename: A
authors.initials: A
authors.lastname: Glasow
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D002196:Capillaries / Q000473:pathology / Q000528:radiation effects; D003324:Coronary Artery Disease / Q000473:pathology*; D003326:Coronary Circulation / Q000528:radiation effects; D003328:Coronary Thrombosis / Q000473:pathology*; D004307:Dose-Response Relationship, Radiation; D004699:Endocardium / Q000473:pathology / Q000528:radiation effects; D006321:Heart / Q000528:radiation effects*; D007249:Inflammation / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000032:analysis; D007964:Leukocytosis / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011833:Radiation Injuries, Experimental / Q000473:pathology*; D018180:Thrombomodulin / Q000032:analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: D001057:Apolipoproteins E; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018180:Thrombomodulin; D019010:Vascular Cell Adhesion Molecule-1; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse