Abstract
Altered cardiac innate immunity is highly associated with the progression of cardiac disease states and heart failure. S100A8/A9 is an important component of damage-associated molecular patterns (DAMPs) that is critically involved in the pathogenesis of heart failure, thus considered a promising target for pharmacological intervention. In the current study, initially, we validated the role of S100A8/A9 in contributing to cardiac injury and heart failure via the overactivation of the β-adrenergic pathway and tested the potential use of paquinimod as a pharmacological intervention of S100A8/A9 activation in preventing cardiac dysfunction, collagen deposition, inflammation, and immune cell infiltration in β-adrenergic overactivation–mediated heart failure. This finding was further confirmed by the cardiomyocyte-specific silencing of S100A9 via the use of the adeno-associated virus (AAV) 9-mediated short hairpin RNA (shRNA) gene silencing system. Most importantly, in the assessment of the underlying cellular mechanism by which activated S100A8/A9 cause aggravated progression of cardiac fibrosis and heart failure, we discovered that the activated S100A8/A9 can promote fibroblast-macrophage interaction, independent of inflammation, which is likely a key mechanism leading to the enhanced collagen production. Our results revealed that targeting S100A9 provides dual beneficial effects, which is not only a strategy to counteract cardiac inflammation but also preclude cardiac fibroblast-macrophage interactions. The findings of this study also indicate that targeting S100A9 could be a promising strategy for addressing cardiac fibrosis, potentially leading to future drug development.
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Abbreviations
- AAV:
-
Adeno-associated virus
- RAGE:
-
Advanced glycation end products
- CSF1:
-
Colony-stimulating factor 1
- DEGs:
-
Differential expression genes
- IL:
-
Interleukin
- MI:
-
Myocardial ischemia
- TNF:
-
Tumor necrosis factor
- BNP:
-
B-type natriuretic peptide
- CANTOS:
-
Canakinumab Anti-inflammatory Thrombosis Outcome Study
- CTnI:
-
Cardiac troponin I
- CCR2:
-
C-C motif receptor 2
- DAMPs:
-
Damage-associated molecular patterns
- ELISA:
-
Enzyme-linked immunosorbent assay
- GO:
-
Gene ontology
- GSEA:
-
Gene set enrichment analysis
- IPA:
-
Ingenuity pathway analysis
- IFN:
-
Interferon
- ISO:
-
Isoprenaline
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- MCP-1:
-
Monocyte chemoattractant protein-1
- MPR14:
-
Myeloid-related protein 14
- NCBI:
-
National Center for Biotechnology Information
- SRA:
-
Sequence Read Archive
- shRNA:
-
Short hairpin RNA
- SMA:
-
Smooth muscle actin
- TLR4:
-
Toll-like receptor 4
- TGF:
-
Transforming growth factor
- WGA:
-
Wheat germ agglutinin
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Funding
This study was funded by the National Natural Science Foundation of China (#82204388 to D. C., #82001693 to X.H., #81773742 and #82273921 to X.L., and # 82104247 to F.W.), Natural Science Foundation of Chongqing (#CSTB2022NSCQ-MSX1446 to D.C.), and Riley Children Foundation (to Y.L. and W.S.).
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DC designed the research; JL, XC, LZ, CP, LZ, XH, SL, and FW performed the research; JL, XC, YL and DC analyzed the data; XC and DC drafted the manuscript; DC, WS, and XL revised and finalized the manuscript. All authors contributed to and have approved the manuscript.
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Liu, J., Chen, X., Zeng, L. et al. Targeting S100A9 Prevents β-Adrenergic Activation–Induced Cardiac Injury. Inflammation (2024). https://doi.org/10.1007/s10753-023-01944-w
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DOI: https://doi.org/10.1007/s10753-023-01944-w