Phenytoin treatment reduces atherosclerosis in mice through mechanisms independent of plasma HDL-cholesterol concentration

Carme Trocho, Joan Carles Escolà-Gil, Vicent Ribas, Sònia Benítez, Jesús M. Martín-Campos, Noemi Rotllan, Lourdes Osaba, Jordi Ordóñez-Llanos, Francesc González-Sastre, Francisco Blanco-Vaca

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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-α. 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. © 2004 Elsevier Ireland Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)275-285
Issue number2
Publication statusPublished - 1 Jun 2004


  • Atherosclerosis
  • Coronary artery disease
  • Drugs
  • Genes
  • High density lipoproteins
  • Microarrays


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