Myocardial infarction-induced microRNA-enriched exosomes contribute to cardiac Nrf2 dysregulation in chronic heart failure

The imbalance between the synthesis of reactive oxygen species (ROS) and their elimination by antioxidant defense systems, results in macromolecular damage and disruption of cellular redox signaling, affecting cardiac structure and function, thus contributing to contractile dysfunction, myocardial hypertrophy and fibrosisinchronic heart failure (CHF). The Keap1-Nrf2 pathway is an important antioxidant defense mechanism and is closely associated with oxidative stress-mediated cardiac remodeling in CHF. In the current study, we investigated the regulation of myocardial Nrf2 in the post myocardial infarction (MI) state. Six weeks post-MI Nrf2 protein was down-regulated in the heart, resulting in a decrease of Nrf2-targeted antioxidant enzymes, whereas paradoxically the transcription of Nrf2 was increased, suggesting that translational inhibition of Nrf2 may contribute to dysregulation of in CHF. We therefore hypothesized that microRNAs may be involved in the translational repression of Nrf2 mRNA in the setting of CHF. Using quantitative real-time PCR analysis, we found that three microRNAs including microRNA-27a, -28-3p and -34a were highly expressed in the left ventricle of infarcted hearts compared to other organs. Furthermore, in vitro analysis revealed that cultured cardiac myocytes and fibroblasts expressed these three microRNAs in response to TNF stimulation. These microRNAs were preferentially incorporated into exosomes and secreted into the extracellular space in which microRNA-enriched exosomes mediated intercellular communication and Nrf2 dysregulation. Taken together, these results suggest that increased local microRNAs induced by myocardial infarction may contribute to oxidative stress by the inhibition of Nrf2 translation in CHF.