Del Nido Cardioplegia or Potassium Induces Nrf2 and Protects Cardiomyocytes Against Oxidative Stress

Abstract

Open heart surgery is often an unavoidable procedure for treatment of cardiovascular disease. Myocardial Ischemia‐Reperfusion Injury can occur as a result of open heart surgery such as cardiopulmonary bypass. The multifaceted mechanisms of MIRI involve the generation of reactive oxygen species (ROS), resulting in cellular damage, ultimately impacting postoperative cardiac performance and complications. Nf‐E2 related factor‐2 (Nrf2), a basic leucine zipper transcription factor, binds to and activates the Antioxidant Response Element (ARE) in the promoters of antioxidant and detoxification genes. We addressed here whether cardioplegic solutions activate Nrf2, therefore serving for cytoprotection. With High K, Low K, Del Nido (DN), histidine‐tryptophan‐ketoglutarate (HTK) and Celsior cardioplegic solutions, we found that High K and DN caused increases of Nrf2 protein in AC16 human cardiomyocytes. Tracing the components in High K and DN led to the finding of K+ at the concentration above 5 mM playing an essential role in Nrf2 protein induction. K+ induced Nrf2 elevation is Ca2+ dependent. ARE luciferase reporter assay confirmed Nrf2 activation by K+ in 10‐40 mM. Profiling transcriptomes using RNA seq showed that oxidation‐reduction process as the main gene ontology group affected by K+. K+induced elevated expression ofclassical downstream targets of Nrf2, including NQO1, AKR, Aldose Reductase, TRXR1, and G6PD. We found that K+ extended the half‐life of Nrf2 from 17.8 mins to 25.1 mins in AC16 cells, and decreased Nrf2 protein ubiquitination. knocking out Keap1 abolished Nrf2 induction by K+. Nrf2 induction by K+ or DN protects cells against loss of viability, apoptosis and ROS production induced by H2O2. Our data support that high K+ concentration in cardioplegic solutions can be cardiac protective via the activation of Nrf2.