The atheroprotective effect of dietary soy isoflavones in apolipoprotein E-/- mice requires the presence of estrogen receptor-alpha.

OBJECTIVE Although the mechanisms by which dietary soy inhibits atherosclerosis are unclear, one line of evidence implicates an important role for its phytoestrogenic isoflavones. We sought to determine whether soy isoflavones exert atheroprotective effects through estrogen receptor-dependent processes and, if so, which estrogen receptor subtype (ie, alpha or beta) is involved. METHODS AND RESULTS We compared the effects of diets rich in soy protein that were either isoflavone depleted (0.04 mg/g protein isolate) or isoflavone-replete, or Soy(+IF) (1.72 mg/g protein isolate) in apolipoprotein E-deficient (ee) mice that had been crossed with estrogen receptor-alpha- and -beta-deficient mice to produce double-knockout alphaalphaee and betabetaee mice and (estrogen receptor) wild-type controls (AAee and BBee). Both male and ovariectomized female mice were studied (n=10 to 17 per treatment group; total n=201). After 16 weeks, atherosclerosis was assessed by quantifying the aortic content of esterified cholesterol. Atherosclerosis was reduced 20% to 27% (P<0.05) by Soy(+IF) in betabetaee, BBee, and AAee mice but was unaffected in alphaalphaee mice. The inhibitory effect of Soy(+IF) was unrelated to sex, total plasma cholesterol, VLDL, LDL, and HDL cholesterol. CONCLUSIONS The results indicate a necessary role for estrogen receptor-alpha-dependent processes in mediating the atheroprotective effects of dietary soy isoflavones.