Grants and Contracts Details
Description
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.
Project Summary/Abstract Page 6
Status | Active |
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Effective start/end date | 7/1/21 → 3/31/26 |
Funding
- University of Nebraska: $1,045,581.00
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