Nrf2 Induction by Cardioplegia and Oxidative Stress

Open heart surgery is often an unavoidable procedure for treatment of cardiovascular disease. Myocardial Ischemia-Reperfusion Injury [1] can occur as a result of cardiopulmonary bypass (CPB), one type of open heart surgery. The multifaceted mechanisms of MIRI involve alteration in metabolism, generation of pro-inflammatory mediators and increases of reactive oxygen species (ROS), ultimately impacting postoperative cardiac performance and complications. Nf-E2 related factor-2 (NRF2), one of the most important regulators for antioxidant response, binds to and activates the Antioxidant Response Element (ARE) in the promoters of many antioxidant and detoxification genes. We addressed whether or not cardioplegic solutions induce the activation of NRF2, therefore serving to protect the myocardium from MIRI. In addition, we also investigated whether cardioplegic solutions affect the baseline cellular metabolism and prevent metabolic reprogramming by oxidative stress. Mechanisms of NRF2 activation involve protein stabilization due to dissociation from KEAP1 or de novo protein translation. When severe stress occurs, Nrf2, as a safeguard against MIRI during CPB, can be translated under a stress condition. We have observed that the 5’ untranslated region (5’UTR) of Nrf2 mRNA enhances its binding with several RNA binding proteins under oxidative stress. We have discovered YTHD2, a YTH domain containing N(6) methyladenosine (m6A) binding protein, increased its association with Nrf2 mRNA and ribosome promoting translation initiation of Nrf2 protein under oxidative stress.