Invited commentary Dietary Nrf2 activators inhibit atherogenic processes Bernhard H.J. Juurlink a, b, * a College of Medicine, University of Saskatchewan, SK, Canada b College of Medicine, Alfaisal University, Riyadh, Saudi Arabia article info Article history: Received 16 August 2012 Received in revised form 23 August 2012 Accepted 25 August 2012 Available online 3 September 2012 Keywords: Anti-oxidant mechanisms Anti-oxidant response element Atherosclerosis Diet Phase 2 protein inducers Sulforaphane abstract Dietary Nrf2 activators increase expression of phase 2 protein genes in cells undergoing oxidative stress resulting in a lowering of oxidative stress. Oxidative stress promotes atherogenic processes through oxidizing low density lipoproteins and promotion of inflammation through activation of nuclear factor kappa B and activation of mitogen-activated protein kinases. Nrf2 activators by decreasing oxidative stress decrease the probability of developing atherosclerotic lesions. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Increased intake of fruits and vegetables has long been recog- nized as being protective against atherosclerosis [1]. Of the vege- tables, epidemiological studies have shown that crucifers have the greatest effect in preventing cardiovascular disease [2]. In this issue of Atherosclerosis J.-S. Kwon et al. examine the ability of sulfor- aphane, a metabolite of sulforaphane glucosinolate present in a number of cruciferous vegetables, to affect mechanisms that are associated with atherogenesis. Sulforaphane is an activator of nuclear factor (erythroid-derived-2)-like-2 (Nrf2) transcription factor [3]. Nrf2 activators, as discussed below, promote a more reducing environment in the cells that are under oxidative stress and sulforaphane’s anti-atherosclerotic effects are likely mediated via promotion of a more reducing environment in the cells and fluids of our body. Before I go further in my commentary I should point out that I am biased towards viewing cellular mechanisms through redox lenses. Caveat lector . Almost 15 years ago Alexander reviewed the evidence that atherosclerosis is a disease of redox sensitive genes [4]. More recently, Hulsman and Holvoet reviewed how oxidative stress and inflammation drive the processes of atherosclerosis [5]. Oxidative stress occurs where a cell can no longer completely scavenge the oxidants that are produced as normal components of cell metabolism, as products of cell injury or as products of activated leukocytes. Aging is associated with an increasing oxidizing envi- ronment [6] due to decreased ability to scavenge oxidants (Fig. 1), mainly because of lower levels of glutathione (GSH), our major redox buffer [7]. This is likely the major factor why atherosclerosis increases with age. Animal studies indicate that decreased GSH concentrations are due mainly to decreased synthetic capabilities [8,9]. Human studies also suggest that decreased GSH levels seen with aging are due mainly to decreased ability to synthesize GSH [10]. Decreased capacity to synthesize GSH correlates with decreased activity of Nrf2 [11,12]. Nrf2 is normally sequestered in the cytoplasm by binding to a protein known as Kelch-ECH-associated protein-1 (Keap1) that orients Nrf2 for ubiquination and subsequent degra- dation by the proteosomal pathway [13]. The association between Nrf2 and Keap1 is mediated via Keap1 thiols that when oxidized no longer allow this association permitting translocation to the nucleus because of nuclear localization signals on Nrf2. In the nucleus Nrf2 heterodimerizes to small Maf proteins allowing binding to anti-oxidant response elements (AREs), thus promoting transcription of the involved genes. Nrf2 also contains nuclear export signals that under reducing conditions dominate over the nuclear localization signals [14] resulting in Nrf2 exclusion from the nucleus. When critical cysteine residues are oxidized in the nuclear export signals, the nuclear localization signals dominate promoting DOI of original article: 10.1016/j.atherosclerosis.2012.07.040. * Permanent address: 683 Butterfield Road, Mill Bay, BC, Canada V0R 2P4. Tel.: þ1 250 885 1656. E-mail addresses: bjuurlink@gmail.com, Jbernhard@alfaisal.edu. Contents lists available at SciVerse ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.08.032 Atherosclerosis 225 (2012) 29e33