Journal article
Single-Nucleus Transcriptomics Identifies Microglial Interferon Regulatory Factor 5 as a Regulator of Neuroinflammation During Heart Failure Progression After Myocardial Infarction in Rats
Journal of the American Heart Association, Vol.15(16), e048110
08/18/2026
DOI: 10.1161/JAHA.125.048110
PMID: 42568060
Abstract
The paraventricular nucleus (PVN) of the hypothalamus is a key autonomic and cardiovascular regulatory center that contributes to neuroinflammation-driven sympathetic excitation in heart failure. To define the cellular and transcriptional mechanisms underlying inflammatory signaling during heart failure progression, we performed single-nucleus RNA sequencing of the PVN in rats 2 weeks after myocardial infarction (MI).
PVN tissues were collected 2 weeks post MI for single-nucleus RNA sequencing analysis. Sequencing data were processed through alignment, dimensionality reduction, clustering, and marker-gene identification to define cell populations and gene expression profiles. Gene Set Variation Analysis and transcriptional regulatory network analyses were performed to identify altered signaling pathways and key transcription factors.
A total of 16 341 nuclei were classified into 5 major cell types: neurons, oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, and microglia. Functional analyses identified microglia as the primary mediators of inflammatory responses in the PVN. Gene Set Variation Analysis revealed substantial pathway alterations across cell types, with microglia exhibiting marked activation of immune-related and cytokine-producing pathways in MI rats. Moreover, IRF5 (interferon regulatory factor 5) was identified as a master transcriptional regulator associated with inflammatory activation and was significantly upregulated in PVN microglia after MI. Increased IRF5 expression in PVN microglia was confirmed by immunofluorescence.
Single-nucleus RNA sequencing identified distinct cell-specific gene signatures, regulatory networks, and signaling pathways in the PVN during heart failure, with microglial IRF5 emerging as a central regulator of immune activation and inflammatory processes. Activated IRF5 promotes microglial activation and neuroinflammation, thereby enhancing PVN neuronal activity and driving sympathetic and neurohumoral dysregulation in rats with MI. Targeting IRF5 and its downstream pathways may therefore provide new insights into the central inflammatory mechanisms contributing to cardiac dysfunction during heart failure progression.
Details
- Title: Subtitle
- Single-Nucleus Transcriptomics Identifies Microglial Interferon Regulatory Factor 5 as a Regulator of Neuroinflammation During Heart Failure Progression After Myocardial Infarction in Rats
- Creators
- Wanxin Tang - University of IowaYang Yu - University of IowaJing-Yu Bing - Shandong Academy of Pharmaceutical SciencesLei Tong - University of IowaRobert M Weiss - University of IowaShun-Guang Wei - Iowa Neuroscience Institute, University of Iowa Iowa City IA USA
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.15(16), e048110
- DOI
- 10.1161/JAHA.125.048110
- PMID
- 42568060
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Publisher
- American Heart Association
- Grant note
- National Heart, Lung, and Blood Institute of the National Institutes of Health: R01 HL-139521, HL-155091, S10-OD038119
This work was supported by research grants from National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers R01 HL-139521 & HL-155091 (to S.- G. Wei), and S10-OD038119 (to R. M. Weiss). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Language
- English
- Electronic publication date
- 08/07/2026
- Date published
- 08/18/2026
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9985218426002771
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