Pharmacological research · 2026
Targeting macrophage-derived oncostatin M preserves cardiomyocyte mitochondrial bioenergetics and contractile function in fulminant myocarditis.
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Yan Yongcui, Sun Zeyu, He Yi, Zhuang Yan, Jiang Jiangang
Аннотация
BACKGROUND: Fulminant myocarditis (FM) is an acute inflammatory cardiomyopathy with high risk of cardiogenic shock. Current management relies largely on circulatory support, while mechanism-based pharmacological targets remain poorly defined.
METHODS: Cardiac CD45+ single-cell RNA sequencing, whole-heart single-nucleus RNA sequencing, ligand-target inference, spatial validation, and human plasma/myocardial analyses were integrated to define disease-associated cellular interactions. CCR2+ macrophage sorting, macrophage depletion, CVB3-stimulated BMDMs, transcription-factor perturbation, ChIP-qPCR, and promoter assays defined the source and regulation of OSM. OSM signaling was examined using recombinant OSM, OSM-neutralizing antibody, macrophage Osm knockdown, cardiomyocyte Osmr silencing, and STAT3/ERK1/2 inhibition, followed by transcriptomic, mitochondrial, contractile, and in vivo analyses.
RESULTS: FM featured expansion of CCR2+ inflammatory macrophages, cardiomyocyte inflammatory/stress remodeling, and enhanced macrophage-to-cardiomyocyte OSM-OSMR signaling. Circulating OSM was increased in patients with FM and correlated with higher NT-proBNP and cTnI and lower LVEF. OSM was produced predominantly by CCR2+ macrophages and transcriptionally induced by IRF1 after CVB3 stimulation. Recombinant OSM aggravated mortality, systolic dysfunction, myocardial inflammation, and cardiac injury. In cardiomyocytes, OSM activated OSMR-dependent STAT3/ERK1/2 signaling and impaired mitochondrial bioenergetics, contractility, and Ca²+ handling. OSM neutralization and macrophage Osm knockdown improved cardiomyocyte respiration and sarcomere shortening after exposure to CVB3-activated macrophage conditioned medium. In vivo, OSM neutralization improved survival, cardiac function, myocardial inflammation, mitochondrial integrity, and ATP content.
CONCLUSION: Macrophage OSM links inflammatory myeloid activation to cardiomyocyte mitochondrial and contractile failure in experimental FM. OSM-OSMR signaling is a candidate mechanism-based pharmacological target for acute inflammatory cardiac dysfunction.
METHODS: Cardiac CD45+ single-cell RNA sequencing, whole-heart single-nucleus RNA sequencing, ligand-target inference, spatial validation, and human plasma/myocardial analyses were integrated to define disease-associated cellular interactions. CCR2+ macrophage sorting, macrophage depletion, CVB3-stimulated BMDMs, transcription-factor perturbation, ChIP-qPCR, and promoter assays defined the source and regulation of OSM. OSM signaling was examined using recombinant OSM, OSM-neutralizing antibody, macrophage Osm knockdown, cardiomyocyte Osmr silencing, and STAT3/ERK1/2 inhibition, followed by transcriptomic, mitochondrial, contractile, and in vivo analyses.
RESULTS: FM featured expansion of CCR2+ inflammatory macrophages, cardiomyocyte inflammatory/stress remodeling, and enhanced macrophage-to-cardiomyocyte OSM-OSMR signaling. Circulating OSM was increased in patients with FM and correlated with higher NT-proBNP and cTnI and lower LVEF. OSM was produced predominantly by CCR2+ macrophages and transcriptionally induced by IRF1 after CVB3 stimulation. Recombinant OSM aggravated mortality, systolic dysfunction, myocardial inflammation, and cardiac injury. In cardiomyocytes, OSM activated OSMR-dependent STAT3/ERK1/2 signaling and impaired mitochondrial bioenergetics, contractility, and Ca²+ handling. OSM neutralization and macrophage Osm knockdown improved cardiomyocyte respiration and sarcomere shortening after exposure to CVB3-activated macrophage conditioned medium. In vivo, OSM neutralization improved survival, cardiac function, myocardial inflammation, mitochondrial integrity, and ATP content.
CONCLUSION: Macrophage OSM links inflammatory myeloid activation to cardiomyocyte mitochondrial and contractile failure in experimental FM. OSM-OSMR signaling is a candidate mechanism-based pharmacological target for acute inflammatory cardiac dysfunction.