The role of Nrf2 in oxidative stress-induced endothelial injuries

Abstract

Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

Protection from cigarette smoke-induced vascular injury by recombinant human relaxin-2 (serelaxin)

“…It can be speculated that RLX may up‐regulate one or more cellular defence mechanisms against oxidative stress through activation of PI3 and MAP kinases, typical downstream pathways of RXFP1 activation in blood vessels 30, 51. These signalling pathways are in fact involved in the cell response to ROS, being able to induce the phosphorylation of the transcription factor nuclear factor‐E2‐related factor 2 (Nrf2), which binds the antioxidant response element within the promoters of genes encoding antioxidant and detoxifying enzymes 52. This hypothesis for the mechanism of action of RLX on cell resistance to oxidative stress deserves further investigation.…”

The effect of Protandim supplementation on oxidative damage and athletic performance.

“…Nrf2 is a protein that regulates the body's antioxidant response to oxidative stress 67,68 . Nrf2 has been called the 'thermostat' within our cells because it can determine the level of oxidative stress and initiate an antioxidant protective response to combat the stress 67,68 .…”

“…Nrf2 has been called the 'thermostat' within our cells because it can determine the level of oxidative stress and initiate an antioxidant protective response to combat the stress 67,68 . Nrf2 activation enables our cells to use their own antioxidant reserve from naturally-occurring and plant-derived activators, such as sulforaphane from broccoli and curcumin from turmeric 67,68 . Some Nrf2 activators are synthetic compounds and thus must be developed by pharmaceutical treatments 67,68 .…”

“…Nrf2 activation enables our cells to use their own antioxidant reserve from naturally-occurring and plant-derived activators, such as sulforaphane from broccoli and curcumin from turmeric 67,68 . Some Nrf2 activators are synthetic compounds and thus must be developed by pharmaceutical treatments 67,68 . New research findings are revealing that the human body's own internal network of antioxidant enzymes is approximately one million times more protective against oxidative stress versus consumption of antioxidant supplements on the market, such as vitamins C and E 67,68 .…”

“…Some Nrf2 activators are synthetic compounds and thus must be developed by pharmaceutical treatments 67,68 . New research findings are revealing that the human body's own internal network of antioxidant enzymes is approximately one million times more protective against oxidative stress versus consumption of antioxidant supplements on the market, such as vitamins C and E 67,68 . Therefore, the future of cellular protection may lie in Nrf2 activation.…”