Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR-/- mice despite severe hypercholesterolemia.
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.
Mueller
Marc A
MA
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstrasse 27, 04103 Leipzig, Germany.
Beutner
Frank
F
Teupser
Daniel
D
Ceglarek
Uta
U
Thiery
Joachim
J
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood; D016207:Cytokines / Q000097:blood; D000068338:Everolimus; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics*; D012720:Severity of Illness Index; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D008078:Cholesterol, LDL; D016207:Cytokines; D007166:Immunosuppressive Agents; D011973:Receptors, LDL; D000068338:Everolimus; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus