Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases

Abstract

The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is highly sensitive to oxidative burst products, including reactive oxygen species (ROS) and reactive nitrogen species. In the cell nucleus, Nrf2 activates various antioxidant genes by binding to the antioxidant response elements. As an adapter for cullin 3/ring-box 1, kelch-like ECH-associated protein 1 (Keap1) ubiquitinates and degrades Nrf2 under physiological conditions. Conversely, with the aggravation of oxidative stress, Keap1-Nrf2 interaction could be much more easily dissociated. ROS play a key role in regulating the redox signaling pathway and affect the vasculature in a dosedependent manner. Long-term production or high concentration of ROS are harmful to the vascular system, while moderate ROS can promote angiogenesis and tissue regeneration. Furthermore, appropriate regulation of oxidative stress mediated via the Keap1-Nrf2 pathway would be beneficial in various diseases associated with abnormal angiogenesis, including diabetes and cancers. Nrf2 deficiency has also been shown to result in significantly impaired survival, proliferation, and angiogenic capacity of endothelial cells in a hind limb ischemia model. Thus, this review will briefly summarize the underlying molecular mechanisms of Keap1-Nrf2 pathway in regulating oxidative stress and also help elucidate the critical role of Keap1-Nrf2 in angiogenesis under physiological and pathological conditions. K E Y W O R D S angiogenesis, diabetes, endothelial cells, Keap1/Nrf2, ROS, tumors

Dimethyl fumarate protects nucleus pulposus cells from inflammation and oxidative stress and delays the intervertebral disc degeneration

“…Nrf2 is an important antioxidant defense factor in the body, expressed in almost all cells. When the body's ROS levels increase, the Nrf2 located in the cytosol is dissociates from its inhibitor Keap1 and is activated (34). Free Nrf2 enters the nucleus and binds to the Maf protein to form a dimer and binds to the antioxidant response element, thereby initiating the transcriptional expression of a series of antioxidant enzymes (35).…”

Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

“…Nrf2 may be involved in diseases associated with insulin resistance [70][71][72] . "Ancient foods", and particularly those containing Lactobacillus , activate Nrf2 69 .…”

“…Nrf2 may be involved in diseases associated with insulin-resistance. 57,[70][71][72] Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases. 73 Nrf2 is involved in the protection against lung 74 or endothelial damage.…”

Sulforaphane: from death rate heterogeneity in countries to candidate for prevention of severe COVID-19

“…26 Nrf2 may be involved in diseases associated with insulin-resistance. 27,28 Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases. Nrf2-activating compounds downregulate ACE2 mRNA expression in human liver-derived HepG2 cells, 29 and in genes encoding cytokines including IL-6 and many others specifically identified in the "cytokine storm" observed in fatal cases of COVID-19.…”