title: Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice.
abstract: OBJECTIVE
  We previously showed that irradiating the carotid arteries of ApoE(-/-) mice accelerated the development of macrophage-rich, inflammatory and thrombotic atherosclerotic lesions. In this study we investigated the potential of anti-inflammatory (atorvastatin, CD40L knockout) and anti-thrombotic (clopidogrel) intervention strategies to inhibit radiation-induced atherosclerosis.
  
  
  METHODS
  ApoE(-/-) mice were given 0 or 14 Gy to the neck and the carotid arteries were harvested at 4 or 28 weeks after irradiation. Atorvastatin (15 mg/kg/day) or clopidogrel (20 mg/kg/day) was given in the chow; control groups received regular chow. Clopidogrel inhibited platelet aggregation by 50%. CD40L(-/-)/ApoE(-/-) and ApoE(-/-) littermates were also given 0 or 14 Gy to the neck and the carotid arteries were harvested after 30 weeks.
  
  
  RESULTS
  Clopidogrel decreased MCP-1 expression in the carotid artery at 4 weeks after irradiation. Expression of VCAM-1, ICAM-1, thrombomodulin, tissue factor and eNOS was unchanged in atorvastatin and clopidogrel-treated mice. Neither drug inhibited either age-related or radiation-induced atherosclerosis. Furthermore, loss of the inflammatory mediator CD40L did not influence the development of age-related and radiation-induced atherosclerosis.
  
  
  CONCLUSIONS
  The effects of radiation-induced atherosclerosis could not be circumvented by these specific anti-inflammatory and anti-coagulant therapies. This suggests that more effective drug combinations may be required to overcome the radiation stimulus, or that other underlying mechanistic pathways are involved compared to age-related atherosclerosis.
authors: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Saske
authors: S
authors: Hoving
authors: Sylvia
authors: S
authors: Heeneman
authors: Marion J J
authors: MJ
authors: Gijbels
authors: Johannes A M
authors: JA
authors: te Poele
authors: Jeffrey F C
authors: JF
authors: Pol
authors: Karen
authors: K
authors: Gabriels
authors: Nicola S
authors: NS
authors: Russell
authors: Mat J A P
authors: MJ
authors: Daemen
authors: Fiona A
authors: FA
authors: Stewart
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D000069059:Atorvastatin; D019013:CD40 Antigens / Q000528:radiation effects; D002339:Carotid Arteries / Q000473:pathology / Q000528:radiation effects; D000077144:Clopidogrel; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000150:complications*; D011897:Random Allocation; D012016:Reference Values; D018709:Statistics, Nonparametric; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D019013:CD40 Antigens; D006538:Heptanoic Acids; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D000077144:Clopidogrel; D013988:Ticlopidine