1. Treatment with KLEPTOSE® CRYSMEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response.
- Author
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Montecucco F, Lenglet S, Carbone F, Boero S, Pelli G, Burger F, Roth A, Bertolotto M, Nencioni A, Cea M, Dallegri F, Fraga-Silva RA, Fougère L, Elfakir C, Gassner AL, Rudaz S, Parissaux X, Wils D, Salomé M, Vuilleumier N, Poggi A, and Mach F
- Subjects
- Animals, Aorta drug effects, Aorta metabolism, Apolipoproteins E metabolism, Atherosclerosis metabolism, Cholesterol metabolism, Cholesterol, HDL metabolism, Disease Models, Animal, Hypercholesterolemia drug therapy, Hypercholesterolemia metabolism, Inflammation drug therapy, Inflammation metabolism, Lipids, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Plaque, Atherosclerotic drug therapy, Plaque, Atherosclerotic metabolism, Th1 Cells metabolism, Triglycerides metabolism, Atherosclerosis drug therapy, Lipid Metabolism drug effects, Th1 Cells drug effects, beta-Cyclodextrins pharmacology
- Abstract
The ability of pharmacological agents to target both "classical" risk factors and inflammation may be key for successful outcomes in the prevention and treatment of atherogenesis. Among the promising drugs interfering with cholesterol metabolism, we investigated whether methyl beta-cyclodextrin (KLEPTOSE® CRYSMEB) could positively impact on atherogenesis, lipid profile and atherosclerotic plaque inflammation in ApoE-/- mice. Eleven-week old ApoE-/- mice were fed either a normal diet (N.D.) or a high-cholesterol diet (H.D.), resulting in different levels of hypercholesterolemia. KLEPTOSE® CRYSMEB (40mg/kg) or vehicle was intraperitoneally administrated 3 times per week in the last 16weeks before euthanasia in mice under N.D. and in the last 11weeks under H.D. Treatment with KLEPTOSE® CRYSMEB reduced triglyceride serum levels in both atherogenesis mouse models. In H.D. mice, treatment with KLEPTOSE® CRYSMEB increased HDL-cholesterol levels and reduced free fatty acids and spleen weight. In both mouse models, treatment with KLEPTOSE® CRYSMEB reduced atherosclerotic plaque size in thoraco-abdominal aortas and intraplaque T lymphocyte content, but did not induce relevant improvements in other histological parameters of vulnerability (macrophage, neutrophil, MMP-9 and collagen content). Conversely and more markedly in H.D. mice, treatment with KLEPTOSE® CRYSMEB was associated with a reduction in genetic markers of Th1-mediated immune response. In vitro, KLEPTOSE® CRYSMEB dose-dependently abrogated Th1 proliferation and IFNγ release. In conclusion, treatment with KLEPTOSE® CRYSMEB reduced atherosclerotic plaque size by improving triglyceride serum levels and Th1-mediated response. These results indicate this drug as a potential tool for blocking atheroprogression associated with different severity degrees of hypercholesterolemia., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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