Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging.

Excessive reactive oxygen species (ROS) generation is as a major cause of oxidative stress and is implicated in cellular dysfunction in aging, cardiovascular disease and other pathologies. As antioxidant trials have largely failed to provide protection in humans, research focus has shifted to activating endogenous antioxidant defenses. In vascular models, activators of the transcription factor NF-E2 related factor 2 (Nrf2) pathway have been shown to restore redox homeostasis by increasing antioxidant/electrophilic response element-mediated (ARE/EpRE) expression of phase II and antioxidant enzymes, including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1) and γ-glutamate cysteine ligase catalytic subunit (GCLC). Nrf2 activators disrupt basal ubiquitin-dependent degradation of Nrf2 by the 26S proteasome, leading to nuclear Nrf2 accumulation and gene induction. This review examines the evidence for crosstalk between Nrf2 and the proteasome, highlighting the mechanisms by which select Nrf2 activators regulate stress-induced proteasomal activity and removal of oxidized proteins. Exploiting the dual action of natural Nrf2 inducers may provide a novel therapeutic strategy for restoring cellular redox homeostasis in aging and cardiovascular related diseases such diabetes, atherosclerosis and stroke.