TY - JOUR
T1 - Treatment with KLEPTOSE® CRYSMEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response
AU - Montecucco, Fabrizio
AU - Lenglet, Sébastien
AU - Carbone, Federico
AU - Boero, Silvia
AU - Pelli, Graziano
AU - Burger, Fabienne
AU - Roth, Aline
AU - Bertolotto, Maria
AU - Nencioni, Alessio
AU - Cea, Michele
AU - Dallegri, Franco
AU - Fraga-Silva, Rodrigo A.
AU - Fougère, Laëtitia
AU - Elfakir, Claire
AU - Gassner, Anne Laure
AU - Rudaz, Serge
AU - Parissaux, Xavier
AU - Wils, Daniel
AU - Salomé, Marc
AU - Vuilleumier, Nicolas
AU - Poggi, Alessandro
AU - Mach, François
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Inflammation
KW - Lipids
KW - Lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=84940747488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940747488&partnerID=8YFLogxK
U2 - 10.1016/j.vph.2015.04.008
DO - 10.1016/j.vph.2015.04.008
M3 - Article
C2 - 25921922
AN - SCOPUS:84940747488
VL - 72
SP - 197
EP - 208
JO - Vascular Pharmacology
JF - Vascular Pharmacology
SN - 1537-1891
ER -