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.
Mann
Giovanni E
GE
Cardiovascular Division, School of Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom. giovanni.mann@kcl.ac.uk
Bonacasa
Barbara
B
Ishii
Tetsuro
T
Siow
Richard Cm
RC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000178:diet therapy* / Q000517:prevention & control; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007529:Isoflavones / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use*; D000072019:Kelch-Like ECH-Associated Protein 1; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology; D045730:Soy Foods
D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D007529:Isoflavones; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016877:Oxidants; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase