ArticleJournal of the American Heart Association2015
Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo.
Article in Journal of the American Heart Association, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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Who cites it
115 citing papers in PubMed, 170 citations in OpenAlex.
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- Cardiac fibroblasts in myocardial injury and heart failure.European heart journal · 2026Review
- Cardiomyocytes HIPK2 regulates myocardial inflammation and heart function through purinergic signaling.Cell communication and signaling : CCS · 2026Article
- T Cell Receptor Repertoires Across the Continuum of Vascular, Myocardial, and Age-Related Diseases.Immunological reviews · 2026Review
- Transient Increase in ATInternational journal of molecular sciences · 2026Article
- Precision immunomodulation of viral myocarditis: a spatiotemporal intervention paradigm based on smart biomaterials.Frontiers in immunology · 2026Review
- Biomolecular mechanisms of cardiac amyloidosis and its cardiovascular pathological basis.Frontiers in immunology · 2026Review
- SCFAs' pleiotropic role in pathogenesis and salutogenesis: mechanisms in exacerbation and regulation of inflammation and fibrosis from gut to host.Journal of medical microbiology · 2026Review
- Review
- Vitamin C in Cardiovascular Disease: From Molecular Mechanisms to Clinical Evidence and Therapeutic Applications.Antioxidants (Basel, Switzerland) · 2025Review
- The immune checkpoint TIM-3/HMGB-1 axis in myocardial infarction.NPJ cardiovascular health · 2025Article
- Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.Nature cardiovascular research · 2025Article
- Galectin-3 in acute myocardial infarction: from molecular mechanisms to clinical translation.Frontiers in molecular biosciences · 2025Review
- The alarmin tandem: unraveling the complex effect of S100A8/A9 - from atherosclerosis to cardiac arrhythmias.Frontiers in immunology · 2025Review
- DAMP sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways.Nature reviews. Immunology · 2024Review
- Unraveling the Mechanisms of S100A8/A9 in Myocardial Injury and Dysfunction.Current issues in molecular biology · 2024Review
- Neutrophil-secreted S100A8/A9 participates in fatty liver injury and fibrosis by promoting myofibroblast migration.Journal of molecular medicine (Berlin, Germany) · 2024Article
- Fibroblast and myofibroblast activation in normal tissue repair and fibrosis.Nature reviews. Molecular cell biology · 2024Review
55 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundTissue injury triggers inflammatory responses that promote tissue fibrosis; however, the mechanisms that couple tissue injury, inflammation, and fibroblast activation are not known. Given that dying cells release proinflammatory "damage-associated molecular patterns" (DAMPs), we asked whether proteins released by necrotic myocardial cells (NMCs) were sufficient to activate fibroblasts in vitro by examining fibroblast activation after stimulation with proteins released by necrotic myocardial tissue, as well as in vivo by injecting proteins released by necrotic myocardial tissue into the hearts of mice and determining the extent of myocardial inflammation and fibrosis at 72 hours. METHODS AND
resultsThe freeze-thaw technique was used to induce myocardial necrosis in freshly excised mouse hearts. Supernatants from NMCs contained multiple DAMPs, including high mobility group box-1 (HMGB1), galectin-3, S100β, S100A8, S100A9, and interleukin-1α. NMCs provoked a significant increase in fibroblast proliferation, α-smooth muscle actin activation, and collagen 1A1 and 3A1 mRNA expression and significantly increased fibroblast motility in a cell-wounding assay in a Toll-like receptor 4 (TLR4)- and receptor for advanced glycation end products-dependent manner. NMC stimulation resulted in a significant 3- to 4-fold activation of Akt and Erk, whereas pretreatment with Akt (A6730) and Erk (U0126) inhibitors decreased NMC-induced fibroblast proliferation dose-dependently. The effects of NMCs on cell proliferation and collagen gene expression were mimicked by several recombinant DAMPs, including HMGB1 and galectin-3. Moreover, immunodepletion of HMGB1 in NMC supernatants abrogated NMC-induced cell proliferation. Finally, injection of NMC supernatants or recombinant HMGB1 into the heart provoked increased myocardial inflammation and fibrosis in wild-type mice but not in TLR4-deficient mice.
conclusionsThese studies constitute the initial demonstration that DAMPs released by NMCs induce fibroblast activation in vitro, as well as myocardial inflammation and fibrosis in vivo, at least in part, through TLR4-dependent signaling.
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