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Protective Effect of the Immunosuppressant Sirolimus Against Aortic Atherosclerosis In Apo E‐Deficient Mice
Author(s) -
Elloso M. Merle,
Azrolan Neal,
Sehgal Suren N.,
Hsu PaLang,
Phiel Kristen L.,
Kopec Caroline A.,
Basso Michael D.,
Adelman Steven J.
Publication year - 2003
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1034/j.1600-6143.2003.00094.x
Subject(s) - sirolimus , medicine , immune system , cholesterol , apolipoprotein e , endocrinology , proinflammatory cytokine , inflammation , apolipoprotein b , immunology , disease
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‐γ and IL‐10 mRNA. In contrast, TGF‐β1 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.