title: Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E-deficient mice.
abstract: Atherosclerosis is a chronic inflammatory disease that develops in response to injury to the vessel wall, and is augmented by hypercholesterolemia. To further delineate the role of the immune system and local factors in this process, we assessed the effects of the immunosuppressant sirolimus (Rapamycin, RAPAMUNE, Wyeth, Collegeville, PA) on atherosclerosis in the apoE-deficient (apoE KO) mouse, a well-accepted model of cardiovascular disease. ApoE KO mice were fed a high fat diet and sirolimus was administered. After 12 weeks, atherosclerotic lesions and plasma lipoproteins were measured. The expression of cytokines associated with atherosclerosis was also examined. All groups demonstrated plasma total cholesterol (TC) >1100 mg/dL. Sirolimus treatment was associated with a 30% increase in LDL-cholesterol (LDLc) and a dose-dependent elevation in HDL-cholesterol (HDLc). Despite increased LDLc, aortic atherosclerosis was markedly reduced in all sirolimus-treated groups. Sirolimus treatment resulted in decreased expression of IL-12p40, IFN-gamma and IL-10 mRNA. In contrast, TGF-beta1 was elevated. Sirolimus significantly reduced atherosclerosis in apo E-KO mice; this effect is independent of, and obviates, elevated plasma TC and LDLc. Sirolimus might therefore be of benefit on atherosclerosis in patients undergoing therapy, independent of any impact on circulating lipids.
authors.affiliation: Cardiovascular-Women's Health Discovery Research, Wyeth Research, Collegeville, PA, USA.
authors.forename: M Merle
authors.initials: MM
authors.lastname: Elloso
authors.forename: Neal
authors.initials: N
authors.lastname: Azrolan
authors.forename: Suren N
authors.initials: SN
authors.lastname: Sehgal
authors.forename: Pa-Lang
authors.initials: PL
authors.lastname: Hsu
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Phiel
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Kopec
authors.forename: Michael D
authors.initials: MD
authors.lastname: Basso
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Adelman
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D001018:Aortic Diseases / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D007166:Immunosuppressive Agents; D012313:RNA; D020123:Sirolimus