Novel Mechanisms of Oxidative Stress Response in Heart Failure

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Novel Mechanisms of Oxidative Stress Response in Heart Failure A large volume of literature indicates an association of oxidative stress with end stage heart failure. Myocardial ischemia or infarction is the most common cause of heart failure, which is difficult to treat and costly to manage, and has a high mortality rate. A deficiency in oxidant removal or damage repair systems in the myocardium may explain the progression of heart failure. At the cellular level, low to mild levels of oxidative stress activate Nrf2 transcription factor to turn on the expression of antioxidant and detoxification genes. We have found that de novo Nrf2 protein translation serves as an important mechanism for Nrf2 activation under oxidative stress. How certain proteins, such as Nrf2, can be selectively translated when cardiac cells encounter oxidative stress remains largely unknown. When investigating the ribosomes using quantitative LC-MS/MS based proteomics, we have recently discovered that YTHD2, a YTH domain containing N6 methyladenosine (m6A) binding protein, increased its association with the ribosomes during oxidative stress. We have found that YTHD2 increases the binding to Nrf2 mRNA and have detected an increase of m6A in Nrf2 mRNA with oxidative stress. Knocking out YTHD2 blocked oxidants from inducing Nrf2 protein. These data lead us to hypothesize that YTHD2 reading of m6A in the Nrf2 5’ untranslated region (5’UTR) serves as a passport for de novo Nrf2 protein translation under oxidative stress. The loss of Nrf2 protein translation mechanisms may contribute to end stage heart failure. Aim 1 will test that oxidative stress causes Nrf2 mRNA methylation at specific sites and m6A landscape change due to activation of METTL3 methylase. Aim 2 will test whether YTHD2 binding causes a Nrf2 5’UTR conformation change and recruitment of a translation initiation complex for de novo Nrf2 protein translation. Aim 3 will demonstrate the losses of stress induced protein translation machinery, regulated mRNA methylation, and Nrf2 mediated cytoprotection in end stage heart failure patients. Our study will advance the knowledge pertaining to a novel discovery involving RNA methylation for de novo protein translation in oxidative stress response. This project will utilize transcriptomic data from heart failure patients to validate mechanistic findings from laboratory research for implications in real life human disease.