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±0.27I, 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.