Nrf2 in early vascular ageing: Calcification, senescence and therapy

Abstract

Under normal physiological conditions, free radical generation and antioxidant defences are balanced, and reactive oxygen species (ROS) usually act as secondary messengers in a plethora of biological processes. However, when this balance is impaired, oxidative stress develops due to imbalanced redox homeostasis resulting in cellular damage. Oxidative stress is now recognized as a trigger of cellular senescence, which is associated with multiple chronic 'burden of lifestyle' diseases, including atherosclerosis, type-2 diabetes, chronic kidney disease and vascular calcification; all of which possess signs of early vascular ageing.Nuclear factor erythroid 2-related factor 2 (Nrf2), termed the master regulator of antioxidant responses, is a transcription factor found to be frequently dysregulated in conditions characterized by oxidative stress and inflammation. Recent evidence suggests that activation of Nrf2 may be beneficial in protecting against vascular senescence and calcification. Both natural and synthetic Nrf2 agonists have been introduced as promising drug classes in different phases of clinical trials. However, overexpression of the Nrf2 pathway has also been linked to tumorigenesis, which highlights the requirement for further understanding of pathways involving Nrf2 activity, especially in the context of cellular senescence and vascular calcification.Therefore, comprehensive translational pre-clinical and clinical studies addressing the targeting capabilities of Nrf2 agonists are urgently required. The present review discusses the impact of Nrf2 in senescence and calcification in early vascular ageing, with focus on the potential clinical implications of Nrf2 agonists and non-pharmacological Nrf2 therapeutics.

Regulation of Vascular Calcification by Reactive Oxygen Species

“…Mammalian cells have evolved endogenous protective mechanisms that counteract ROS generation. Nuclear factor erythroid 2-related factor 2 (Nrf2), is a key regulator of such protective responses, and recent evidence suggests that activation of Nrf2 may be beneficial in attenuating vascular calcification [ 191 ]. In the canonical Nrf2 pathway under normal conditions, Nrf2 is suppressed by Kelch-like ECH-associated protein 1 (Keap1), which leads to ubiquitylation and proteasomal degradation of Nrf2 [ 192 ].…”

Epigallocatechin Gallate Effectively Affects Senescence and Anti-SASP via SIRT3 in 3T3-L1 Preadipocytes in Comparison with Other Bioactive Substances

“…EGCG, phloretin, and related substances have the potential to induce NRF2 , but only anthocyanidin and resveratrol could significantly increase NRF2 in our study [ 16 ]. NRF2 is a stress responsive transcription factor balancing redox homeostasis by activating genes that encode cytoprotective, antioxidant, and phase II detoxifying enzymes [ 16 , 32 ]. Several natural compounds have been identified as electrophilic NRF2 inducers, like resveratrol, as we could also demonstrate in our results [ 33 ].…”

“…Latter activation is either due to oxidative stress or other NRF2 activators. Following this, NRF2 translocate from the cytoplasm into the nucleus and binds to ARE of different genes [ 32 , 37 ]. Butyrate, but also BHB, has been shown to be potent NRF2 activators in different studies [ 38 – 40 ].…”

“…Although IL6 levels decreased in senescent cells after most polyphenol treatments, our results suggest that this is not only by reason of NRF2 activation but rather, due to a direct activation of SIRT3 . However, NRF2 activation is depending on the chemical structure of the bioactive compounds [ 14 , 32 ]. Interestingly, SIRT 3 activity can reduce ROS levels by directly modulating key antioxidant enzymes, thereby acting as a shield against oxidative damage.…”

Hydrogen Sulfide Protects Against Ammonia-Induced Neurotoxicity Through Activation of Nrf2/ARE Signaling in Astrocytic Model of Hepatic Encephalopathy

“…This self-amplifying cycle between astrocyte swelling and OxS results in neuronal dysfunction, ranging from trivial lack of awareness to coma (Häussinger et al, 1994, Häussinger, 2006Zielińska et al, 2003;Reinehr et al, 2007). Nuclear factor erythroid 2-related factor 2 (Nrf2), termed the master regulator of antioxidant responses, is a transcription factor found to be frequently dysregulated in OxS (Arefin et al, 2020). During OxS, the static binding between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm is dissociated, which allows the translocation of Nrf2 into the nucleus, and Nrf2 interacts with the antioxidant response element (ARE) to initiate the transcription of target genes to alleviate OxS (Shen et al, 2015).…”