Phenytoin treatment reduces atherosclerosis in mice through mechanisms independent of plasma HDL-cholesterol concentration.
Phenytoin (PHT) increases high density lipoprotein cholesterol (HDL-C) and reduces coronary artery disease mortality in humans. We report the results of PHT treatment on atherosclerosis susceptibility and lipid profile in four different types of mouse: control C57BL/6 mice and cholesteryl ester transfer protein transgenic mice as models of fatty streak, and LDL receptor-deficient mice and apolipoprotein E-deficient mice as models of mature atherosclerosis. Each mouse type was fed an appropriate diet to induce atherosclerosis and prevent liver toxicity. PHT treatment demonstrated a protective effect in all models. Reduction in aortic atherosclerotic area by PHT treatment was more evident in early atherosclerosis (2.3-fold) than in mature atherosclerosis (decreases of 40 and 23%, respectively, but only in mice in the upper 50% percentile of plasma PHT concentration). Atherosclerosis prevention was not concomitant with a consistent increase in HDL-C or any other protective change in the lipid profile. Different analyses of potential antiatherogenic HDL functions did not provide additional information. Microarray liver gene expression analyses identified a potential atheroprotective mechanism characterized by decreased expression of syndecan-4, RhoA2, double LIM protein-1, zeta-chain-associated protein kinase-70 and interleukin 6 receptor-alpha. However, to demonstrate that these changes are part of a PHT-antiatherogenic effect, they will need to be found also in arteries, maintained at protein level and proved to be causal rather than reactive.
Trocho
Carme
C
Servei de Bioquímica, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
Escolà-Gil
Joan Carles
JC
Ribas
Vicent
V
Benítez
Sònia
S
Martín-Campos
Jesús M
JM
Rotllan
Noemi
N
Osaba
Lourdes
L
Ordóñez-Llanos
Jordi
J
González-Sastre
Francesc
F
Blanco-Vaca
Francisco
F
D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000235:genetics; D008076:Cholesterol, HDL / Q000187:drug effects* / Q000235:genetics; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010672:Phenytoin / Q000378:metabolism / Q000494:pharmacology*; D011336:Probability; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D013045:Species Specificity; D018709:Statistics, Nonparametric; D015854:Up-Regulation
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D010672:Phenytoin; D012313:RNA