Targeting the redox sensitive Nrf2-Keap1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones

Cells have evolved highly regulated defense systems, including the redox sensitive Nrf2-Keap1 signaling pathway involved in the transcriptional activation of phase II defense and antioxidant genes in oxidative stress. Increased generation of reactive oxygen species (ROS) in cardiovascular disease (CVD) leads to impaired endothelial function and reduced nitric oxide (NO) bioavailability. Although epidemiological evidence suggests that diets containing plant-derived isoflavones (phytoestrogens) afford protection against CVDs, supplementation trials have largely reported only marginal health benefits. The molecular mechanisms by which soy isoflavones (genistein, daidzein, and equol) afford protection against oxidative stress in CVD remain to be investigated in large-scale clinical trials. Studies in animal models and cultured vascular cells have established that isoflavones increase eNOS activity and expression and activate the Nrf2-Keap1 signaling pathway, leading to an upregulation of detoxifying and antioxidant defense genes. We review recent advances in the understanding of the signal transduction pathways involved in the activation of endothelial NO production and Nrf2-Keap1-mediated antioxidant gene expression by dietary isoflavones.