Nrf2 regulation of oxidative stress in heart failure and extra vesicular communication

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PROJECT SUMMARY/ABSTRACT Despite progress in the management of chronic heart failure (CHF), it remains a leading cause of mortality and morbidity worldwide. A reduction in Nrf2 signaling has been closely associated with oxidative stress-mediated cardiac remodeling and sympathetic excitation in the pathogenesis of CHF. However, there are several critical gaps in our current knowledge of the molecular mechanisms of Nrf2 signaling dysregulation and cross-talk between the heart and brain in CHF. Here our long-term goal is to understand a unique mechanism by which Nrf2 signaling is impaired through intra- and inter-organ communication in CHF. In previous studies we showed the potential involvement of miRNAs and extracellular vesicles (EVs) in Nrf2 dysregulation in CHF. EV-enriched miRNAs have recently emerged as regulators of intercellular communication and paracrine signaling mediators during physiological and pathological processes in the cardiovascular system. These findings led to the central hypothesis that myocardial infarction (MI) induces the preferential secretion of miRNA-enriched EVs from cardiac cells into the extracellular space where EV-miRNAs either directly contribute to increased local oxidative stress via intercellular communication, or circulate to the CNS evoking sympathetic excitation by disrupting central redox homeostasis due to a reduction in Nrf2 signaling. We have identified several miRNAs that target Nrf2 mRNA and are selectively upregulated in cardiac cells and contained in EVs that are secreted into the extracellular space. We also provide evidence that cardiac-derived EVs and Nrf2-targeting miRNAs are present in sympatho-regulatory areas of the brain. Guided by this strong preliminary data, we propose to pursue three Specific Aims: 1) To determine if EV-enriched miRNAs contribute to Nrf2 translational inhibition and redox imbalance through intercellular communication in the heart in the CHF state; 2) To determine if cardiac derived EVs participate in inter-organ communication, especially cross-talk between the heart and brain in the progression of CHF, and 3) To determine if circulating EVs from CHF animals transfer a pathophysiological phenotype in sympatho-regulatory areas of the brain. This aim will also evaluate if EV-mediated miRNA inhibitor delivery (i.e. antagomirs) attenuates the CHF phenotype by inhibition of the decrease in Nrf2 and antioxidant enzyme signaling. Collectively, the proposed research is innovative because it pursues the novel idea that miRNA-enriched EVs contribute to increased oxidative stress at the local level and in remote sympatho- regulatory areas of the brain via EV-mediated communication by disrupting redox homeostasis in the CHF state. This novel communication pathway may help to explain how sympathetic nerve activity increases in the post MI state independent of classical neural pathways. Incorporation of human tissue into these studies will provide a unique translational component and potentially lead to new therapies and interventions in CHF.