Treatment with KLEPTOSE® CRYSMEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response

Fabrizio Montecucco, Sébastien Lenglet, Federico Carbone, Silvia Boero, Graziano Pelli, Fabienne Burger, Aline Roth, Maria Bertolotto, Alessio Nencioni, Michele Cea, Franco Dallegri, Rodrigo A. Fraga-Silva, Laëtitia Fougère, Claire Elfakir, Anne Laure Gassner, Serge Rudaz, Xavier Parissaux, Daniel Wils, Marc Salomé, Nicolas VuilleumierAlessandro Poggi, François Mach

Research output: Contribution to journalArticlepeer-review

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 (40. mg/kg) or vehicle was intraperitoneally administrated 3 times per week in the last 16. weeks before euthanasia in mice under N.D. and in the last 11. weeks 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.

Original languageEnglish
Pages (from-to)197-208
Number of pages12
JournalVascular Pharmacology
Volume72
DOIs
Publication statusPublished - Sep 1 2015

Keywords

  • Atherosclerosis
  • Inflammation
  • Lipids
  • Lymphocytes

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Physiology

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