Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice

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• 作者：Frank Beutner^a ; ^b ; ¹ ; ^{frank.beutner@medizin.uni-leipzig.de} ; Dé ; siré ; Brendel^a ; ¹ ; Daniel Teupser^a ; ^b ; ^c ; Kristina Sass^a ; Ronny Baber^a ; ^b ; Marc Mueller^a ; ^d ; Uta Ceglarek^a ; ^b ; Joachim Thiery^a ; ^b
• 关键词：Everolimus ; mTOR ; Mammalian target of rapamycin ; Atherosclerosis ; PSI ; Proliferation signal inhibitor ; Hypercholesterolemia ; Stage-dependent efficiency of treatment
• 刊名：Atherosclerosis
• 出版年：2012
• 期刊代码：28_00219150
• 类别：med
• 出版时间：June, 2012
• 卷：222
• 期：2
• 页码：337-343
• 文件大小：993 K

摘要

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.

Methods and 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 卤 0.02 vs. 0.33 卤 0.03 mm², p = ns) and brachiocephalic lesions (0.044 卤 0.006 vs. 0.066 卤 0.012 mm², p = ns) but without significance. Everolimus (5 mg/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.

Conclusion

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.