Despite decades of study, the cardioprotective component(s) of soy and the means by which they exert their effects remains unclear. An accumulating body of evidence indirectly implicates equol, the major metabolite of the soy isoflavone daidzein, as having substantial cardioprotective activity. However, equol is produced from daidzein by the activity of bacterial enzymes in the lower Gl tract, and little is known about its biological activity in vivo. In the proposed studies, the athero-inhibitory activity of equol will be addressed directly using germ-free and human flora-associated apoE null (atherosclerosis-susceptable) mice. In addition, evidence from our lab demonstrates a marked athero-inhibitory effect of concentrated 7S fraction, a storage protein that accounts for about 30% of the protein in soy beans. The possibility that there are additive/interactive effects of nutrients that could enhance the cardiovascular benefits of soy supplements in human beings has received little attention. The studies proposed here will address further the individual and additive/interactive influence of isoflavones and 7S fraction on the development of atherosclerotic plaques. Assessments will also be made of morphologic and morphometric characteristics associated with plaque vulnerability. Finally, since the pathways through which isoflavones and 7S globulin mediate antiatherosclerotic effects are uncertain and do not appear to depend on effects on plasma lipoproteins, 1) the effects of these interventions on oxidative and inflammatory pathways implicated in atherosclerosis will be studied and 2) using DNA micro-array and qRT-PCR techniques, candidate genes will be identified for further investigation into pathways through which atheroprotective effects of soy and its components are mediated. Since only about 1/3 of American human beings produce equol, the results will provide evidence to indicate whether it may be advantageous to explore 1) probiotic approaches to inducing equol production in non-producer human beings, 2) the use of concentrated equol or certain soy protein fractions in dietary supplements and 3) the combined use of both peptides and isoflavones in dietary supplements.
