Treatment with KLEPTOSE® CRYSMEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response.
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.
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy; Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland; Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland. Electronic address: Fabrizio.montecucco@unige.ch.
Fabrizio
F
Montecucco
Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland.
Sébastien
S
Lenglet
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy; Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland.
Federico
F
Carbone
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy.
Silvia
S
Boero
Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland.
Graziano
G
Pelli
Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland.
Fabienne
F
Burger
Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland.
Aline
A
Roth
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy.
Maria
M
Bertolotto
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy.
Alessio
A
Nencioni
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy.
Michele
M
Cea
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy.
Franco
F
Dallegri
Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Rodrigo A
RA
Fraga-Silva
Institut de Chimie Organique et Analytique CNRS-UMR 7311, University of Orleans, F-45067 Orléans cedex 02, France.
Laëtitia
L
Fougère
Institut de Chimie Organique et Analytique CNRS-UMR 7311, University of Orleans, F-45067 Orléans cedex 02, France.
Claire
C
Elfakir
School of Pharmaceutical Sciences, University of Geneva, 30, quai Ernest-Ansermet, 1211 Geneva, Switzerland.
Anne-Laure
AL
Gassner
School of Pharmaceutical Sciences, University of Geneva, 30, quai Ernest-Ansermet, 1211 Geneva, Switzerland.
Serge
S
Rudaz
Roquette Frères, 62080 Lestrem cedex, France.
Xavier
X
Parissaux
Roquette Frères, 62080 Lestrem cedex, France.
Daniel
D
Wils
Cabinet d'Etudes et Concepts, Ramonville, France.
Marc
M
Salomé
Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.
Nicolas
N
Vuilleumier
Unit of Molecular Oncology and Angiogenesis, IRCCS Azienda Ospedaliera Universitaria San Martino-IST National Institute for Cancer Research, 16132 Genoa, Italy.
Alessandro
A
Poggi
Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland.
François
F
Mach
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008055:Lipids; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology*
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008055:Lipids; D014280:Triglycerides; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol
Atherosclerosis; Inflammation; Lipids; Lymphocytes