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

Magdalena P Kasprzak,Bogna Gryszczyńska,Magdalena Budzyń,Anna Olasińska-Wiśniewska,Maciej Lesiak,Maria Iskra,Olga Trojnarska,Reiko Matsui

doi:10.1155/2020/8249729

Magdalena P Kasprzak, Bogna Gryszczyńska + Show 6 more

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https://doi.org/10.1155/2020/8249729

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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.

Highlights

Nuclear factor erythroid 2-related factor2 (Nrf2) is a transcription factor managing the phase II response to oxidative stress by inducing the variety of antioxidant enzymes
Further multiple comparisons revealed the significant reduction in total antioxidant capacity (TAC) after percutaneous coronary intervention (PCI) due to ischemia-induced oxidative stress when compared with the previous state and a significant increase in the following step (24 h-left main stenting via percutaneous coronary intervention (LMPCI)) of the experiment (Figure 2)
We may conclude that ischemia induced by the PCI was the source of imbalance in the Nrf2/Kelch-like ECH-associated protein 1 inhibitor (Keap1) ratio via oxidative stress and inflammation, which leads to the increase in PON1 concentration first and the TAC mobilization in the step

Summary

Introduction

Nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor managing the phase II response to oxidative stress by inducing the variety of antioxidant enzymes. It modulates the expression of genes controlling the inflammatory and immune system response [1,2,3]. Nrf has dissociated from its Kelch-like ECH-associated protein 1 inhibitor (Keap1) and translocated into the nucleus [1,2,3]. Nrf promoting mechanism involves binding to the antioxidant response element (ARE) in the promoter region of several adaptive genes such as glutathione-S-transferase (GST), γ-glutamyl cysteine, heme oxygenase 1(HO-1), and paraoxonase-1 (PON1) [4,5,6].

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