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.
Footnotes
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This work was supported by a Novartis Pharma AG, Basel, Switzerland research grant and the University of Milan [Grant FIRST 2007].
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Parts of this work were previously presented at the following conferences: Bellosta S, Baetta R, Ferri N, Arnaboldi L, Canavesi M, Pfister P, Granata A, Dorent R, and Corsini A (2007) Poster 218. 76th Annual European Atherosclerosis Society Congress; 2007 10–13 June; Helsinki, Finland. European Atherosclerosis Society, Malmö, Sweden; and Bellosta S, Baetta R, Canavesi M, Ferri N, Arnaboldi L, Pfister P, Granata A, Dorent R, and Corsini A (2007) XVI International Symposium on Drugs Affecting Lipid Metabolism. 2007 4–7 October; New York.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144147.
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ABBREVIATIONS: mTOR, mammalian target of rapamycin; SMC, smooth muscle cell; CCL2 (MCP-1), monocyte chemoattractant protein-1; fMLP, N-formyl-Met-Leu-Phe; rh, recombinant human; CX3CL1, fractalkine; C5a, complement fragment 5a; CXCL8 (IL-8), interleukin-8; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; HC, high cholesterol; FPLC, fast protein liquid chromatography; PBS, phosphate-buffered saline; H&E, hematoxylin and eosin; I/M, intima-media area ratio; DMEM, Dulbecco's modified Eagle's medium; PI, propidium iodide; TC, total cholesterol.
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↵1 Current affiliation: NicOx SA, Sophia Antipolis, France.
- Received July 29, 2008.
- Accepted November 19, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Everolimus Inhibits Monocyte/Macrophage Migration in Vitro and Their Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits
