title: Nrf2-mediated redox signalling in vascular health and disease.
abstract: Cells have evolved endogenous defence mechanisms to counteract oxidative stress, and the redox sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the defence against oxidative stress via the induction of phase II and antioxidant enzymes.1-3 Under low oxidative or nitrosative stress, Nrf2 is sequestered by its cytosolic binding protein Kelch-like ECH Associated Protein 1 (Keap1) and targeted for proteasomal degradation.4 GSK-3β phosphorylation may also lead to Nrf2 degradation via an adaptor protein β-TrCP independent of Keap1.5 Modification of Keap1 cysteine residues leads to nuclear accumulation of Nrf2 via de novo synthesis, and in the nucleus Nrf2 binds to a Maf recognition/antioxidant response element in the promoter of phase II and antioxidant genes, such as NQO1, HO-1, and glutamate cysteine ligase and cystine transporter xCT involved in glutathione synthesis. Our studies in wild type and Nrf2-/- murine macrophages identified Nrf2 as an important transcription factor involved in the induction of CD36 and antioxidant stress genes in atherosclerosis.2 Notably, Nrf2 regulated redox signalling and antioxidant defences in response to hydroxynonenal are impaired in fetal umbilical vein endothelial and artery smooth muscle cells isolated from gestational diabetic and pre-eclamptic pregnancies.6,7 More recently, we have shown that pretreatment of rodents with the Nrf2 inducer sulforaphane increases Nrf2 mediated HO-1 expression in neurovascular unit after a stroke, maintaining blood-brain barrier (BBB) integrity and neurological function.8 Targeting the Nrf2 defence pathway using pharmacological and/or dietary inducers may provide a therapeutic approach to prevent oxidative stress induced damage in the peripheral vasculature or the BBB in stroke.Supported by British Heart Foundation, Heart Research UK, Henry Smith Charity.
authors.affiliation: Cardiovascular Division, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, UK.. Electronic address: giovanni.mann@kcl.ac.uk.
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Mann