title: Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits.
abstract: Monocytes/macrophages recruited into the arterial wall during atherogenesis are crucial in the initiation and progression of atherosclerosis and play a fundamental role in the destabilization process that is the main causal event of acute coronary syndromes. In the present study, we investigated the effect of the mammalian target of rapamycin inhibitor everolimus on macrophage accumulation within carotid lesions elicited by perivascular collar placement in cholesterol-fed rabbits. Everolimus (1.5 mg/kg given 1 day before collaring followed by 1 mg/kg/day for 14 days, administered by oral gavage) markedly decreased lesion macrophage content as compared with vehicle control (-65%; p < 0.01). This effect was associated with a reduction in intimal thickening and occurred in the absence of changes in plasma cholesterol concentrations. To gain insights on the potential mechanism(s) underlying this effect, we investigated the influence of everolimus on chemoattractant-induced migration of human monocytes in vitro. Pretreatment with therapeutic concentrations of everolimus (10 nM) significantly lowered monocyte chemotaxis in response to various chemotactic factors (i.e., monocyte chemoattractant protein-1/CCL2, fractalkine/CX3CL1, interleukin-8/CXCL8, complement fragment 5a, or N-formyl-Met-Leu-Phe) without inducing monocyte cell death. These results suggest that everolimus may favorably influence the atherosclerotic process by affecting the recruitment of monocytes into early lesions.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. roberta.baetta@unimi.it
authors.forename: Roberta
authors.initials: R
authors.lastname: Baetta
authors.forename: Agnese
authors.initials: A
authors.lastname: Granata
authors.forename: Monica
authors.initials: M
authors.lastname: Canavesi
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Arnaboldi
authors.forename: Stefano
authors.initials: S
authors.lastname: Bellosta
authors.forename: Pascal
authors.initials: P
authors.lastname: Pfister
authors.forename: Alberto
authors.initials: A
authors.lastname: Corsini
mesh_terms: D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002630:Chemotactic Factors / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology*; D000068338:Everolimus; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D002630:Chemotactic Factors; D007166:Immunosuppressive Agents; D002784:Cholesterol; D000068338:Everolimus; D020123:Sirolimus