title: Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice.
abstract: OBJECTIVE
  Proliferation signal inhibitors/mTOR-inhibitors have been shown to reduce de novo development of hypercholesterolemic atherosclerosis in animal models. However, their effect on pre-existing atherosclerosis has not yet been studied.
  
  
  RESULTS
  Feeding LDL-R-KO mice a high cholesterol diet for 12 weeks resulted in formation of moderate fibroatheroma (induction phase). Sixty mice received either everolimus (1 or 5 mg/kg) or no everolimus for further 12 weeks (treatment phase). Everolimus significantly enhanced hypercholesterolemia (plasma cholesterol +45%, p<0.001). Atherosclerosis progressed obstructively in treated and non-treated mice. Everolimus (5 mg/kg) tended to reduced progression in aortic root lesions (0.28±0.02 vs. 0.33±0.03 mm(2), p=ns) and brachiocephalic lesions (0.044±0.006 vs. 0.066±0.012 mm(2), p=ns) but without significance. Everolimus (5mg/kg) resulted in an arrest of CD68 positive plaque area (p=0.03) and nearly halved CD68 fraction (p=0.05) in aortic root lesions but not in brachiocephalic lesions. Taken together, despite a trend to reduced progression and inflammatory cell content there was less conclusive net effect of everolimus treatment than expected.
  
  
  CONCLUSIONS
  A higher potential of everolimus in the treatment of atherosclerosis might be obscured by its concomitant hypercholesterolemia. Considering stronger effects in previous studies we suggest that everolimus might exert more potent anti-atherogenic properties in earlier stages of atherogenesis than in advanced atherosclerosis.
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Leipzig, Germany. frank.beutner@medizin.uni-leipzig.de
authors.forename: Frank
authors.initials: F
authors.lastname: Beutner
authors.forename: Désiré
authors.initials: D
authors.lastname: Brendel
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.forename: Kristina
authors.initials: K
authors.lastname: Sass
authors.forename: Ronny
authors.initials: R
authors.lastname: Baber
authors.forename: Marc
authors.initials: M
authors.lastname: Mueller
authors.forename: Uta
authors.initials: U
authors.lastname: Ceglarek
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D016122:Brachiocephalic Trunk / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D000068338:Everolimus; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D002784:Cholesterol; D000068338:Everolimus; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C546843:mTOR protein, mouse