Protein Translation for Oxidative Stress Response in Heart Failure

A large volume of literature indicates an association of oxidative stress with the causes or progression of heart failure. Heart failure is difficult to treat and costly to manage, yet carries a high mortality rate. Among the most common causes of heart failure is myocardial ischemia or infarction. Lack of endogenous oxidant removal or damage repair systems 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. Works from our laboratory has demonstrated that de novo Nrf2 protein translation serves as an important mechanism for Nrf2 activation under oxidative stress. It is well established that stress causes a general inhibition of protein translation. How certain proteins, such as Nrf2, can escape the general control and be selectively translated when cardiac cells encounter oxidative stress is largely unknown. When investigating the translation machinery using quantitative LC-MS/MS based proteomics, we have discovered that YTHD2, a YTH domain containing N6 methyladenosine (m6A) binding protein, increased 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 due to oxidative stress. Knocking out YTHD2 blocked oxidants from inducing Nrf2 protein. These data lead us to hypothesize that YTHD2 reading of m6A in Nrf2 mRNA serves as a passport for de novo Nrf2 protein translation under oxidative stress. The loss of stress associated protein translation mechanisms contributes to the progression from cardiac injury to heart failure. Aim 1 will test whether YTHD2 causes recruitment of a translation initiation complex for de novo protein translation under oxidative stress. Aim 2 will test that oxidative stress causes methylation at specific sites of Nrf2 mRNA and m6A landscape change due to activation of METTL3 methylase. Aim 3 will demonstrate the loss of stress associated translation machinery during the progression from ischemic injury to heart failure. 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 animal models of heart failure, and transcriptomic data from human heart failure patients to validate mechanistic findings for implications in real life human disease. Project Number: 1R01HL179676-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: QIN CHEN | Institution: UNIVERSITY OF ARIZONA, TUCSON, AZ | Award Amount: $576,786 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17967601