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.