Changes in the Nrf2/Keap1 Ratio and PON1 Concentration in Plasma of Patients Undergoing the Left Main Coronary Artery Stenting

Abstract

Nuclear factor erythroid 2-related factor2 (Nrf2), together with its inhibitor Kelch-like ECH-associated protein 1 (Keap1), is a crucial regulator of cellular redox response. Nrf2 binds to the antioxidant response element (ARE) present in the DNA sequence of a broad group of antioxidant compounds, including paraoxonase (PON1), inducing their transcription. This study was to answer the question of the effect of temporary ischemia/oxidative stress resulting from the left main stenting via percutaneous coronary intervention (LMPCI) performed in the patients included in this study on the cellular redox balance, which is guarded by the Nrf2/Keap1 interaction. We expected a reflection of the redox imbalance due to reactive oxygen species (ROS) in the change in PON1 concentration observed in the following stages of the study, as well as in total antioxidant capacity (TAC) levels. Our results showed the mobilization of cellular Nrf2/Keap1 team right after the procedure (pre-LMPCI median: 2.532, range: 0.07-11.88; post-LMPCI median: 3.735, range: 0.1545-16.18; 24 h-LMPCI median: 5.596, range: 0.02-49.18), which suggest being the result of oxidative stress that accompanies percutaneous coronary intervention (PCI). The course of Keap1 and Nrf2 concentrations at all stages of the experiment appeared to show that Keap1 shadowed the Nrf2 to switch off its activity after Nrf2 induced the mobilization of the antioxidant response. We observed an increase in PON1 concentration (pre-LMPCI median: 179.3, range: 49.76-6120; post-LMPCI median: 215.7, range: 3.80-2771) and a decrease in the TAC level immediately after PCI (pre-LMPC: 1.008 ± 0.27 I , post-LMPCI: 0.8030 ± 0.27 ). This study design allowed for the first time to analyze the chronology of mechanisms and the relationship between selected parameters reflecting the redox state in patients’ plasma. We may conclude that ischemia induced by the PCI was the source of imbalance in the Nrf2/Keap1 ratio via oxidative stress, and this leads to an increase in PON1 concentration first and, in the next step, the TAC mobilization.

Blb-NRF2-PON1 Cross-Talk in Abdominal Aortic Aneurysm Progression

“…The multivariate linear regression revealed that bilirubin and NRF2 were independent predictors of PON1 concentration in the study group. The continuing trend of increasing PON1 concentration with increasing aneurysm size may also refer to its role as an acute phase protein, which has already been described in our previous work [ 26 ]. Studies by Burillo et al indicate that the concentration of PON1 in patients with AAA is 2.5 times lower than in the control group [ 19 ].…”

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

“…Oxidative stress responses clarified the functioning of central principal switches like nuclear factor (NF)-κB (NFκB) or the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway ( Sies, 2015 ; Yamamoto et al, 2018 ; Cuadrado et al, 2019 ; Herengt et al, 2021 ). Under oxidative stress and induced by excessive ROS generation, Nrf2 is released from its inhibitor Keap1, allowing its translocation into the nucleus ( Kasprzak et al, 2020 ), where it binds to the antioxidant response element (ARE) present in the DNA sequence of numerous antioxidant enzymes like glutathione-S-transferase, γ-glutamyl cysteine synthetase (glutamate cysteine ligase), heme oxygenase 1, and paraoxonase-1 inducing their transcription, managing the phase II response to oxidative stress ( Kasprzak et al, 2020 ). Nrf2 also regulates the expression of genes that control inflammatory and immune system responses ( Kasprzak et al, 2020 ).…”

“…Under oxidative stress and induced by excessive ROS generation, Nrf2 is released from its inhibitor Keap1, allowing its translocation into the nucleus ( Kasprzak et al, 2020 ), where it binds to the antioxidant response element (ARE) present in the DNA sequence of numerous antioxidant enzymes like glutathione-S-transferase, γ-glutamyl cysteine synthetase (glutamate cysteine ligase), heme oxygenase 1, and paraoxonase-1 inducing their transcription, managing the phase II response to oxidative stress ( Kasprzak et al, 2020 ). Nrf2 also regulates the expression of genes that control inflammatory and immune system responses ( Kasprzak et al, 2020 ). The presence of Nrf2 and its inhibitor Keap1 in plasma is associated with damaged vascular endothelial cell-, macrophage-and other cell-associated leakage secondary to the loss of cell membrane integrity due to lipid peroxidation following chronic inflammation and oxidative stress ( Kasprzak et al, 2020 ), and Nrf2 and Keap1 in circulation are markers of severe inflammation and oxidative stress ( Tu et al, 2019 ).…”

“…Nrf2 also regulates the expression of genes that control inflammatory and immune system responses ( Kasprzak et al, 2020 ). The presence of Nrf2 and its inhibitor Keap1 in plasma is associated with damaged vascular endothelial cell-, macrophage-and other cell-associated leakage secondary to the loss of cell membrane integrity due to lipid peroxidation following chronic inflammation and oxidative stress ( Kasprzak et al, 2020 ), and Nrf2 and Keap1 in circulation are markers of severe inflammation and oxidative stress ( Tu et al, 2019 ). Continuous oxidative stress can lead to chronic inflammation, intense cytokine release and a cytokine storm as seen in SARS-CoV-2 infection in COVID-19 disease, and the viral infection enhances oxidative stress creating a fatal vicious circle between oxidative stress and cytokine storm during COVID-19 infection ( Delgado-Roche and Mesta, 2020 ; Meftahi et al, 2021 ).…”