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Atherosclerosis. 2008 May;198(1):39-48. Epub 2007 Nov 5.

Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia.

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1
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstrasse 27, 04103 Leipzig, Germany.

Abstract

Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR(-/-)) mice. Male hypercholesterolemic LDLR(-/-) mice received either solvent (group A; n=28) or everolimus at 0.05 mg/kg (group B, n=22) and 1.5 mg/kg (group C, n=29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p<0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques.

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