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

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 +/- 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 (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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.