Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction
Abstract
Background In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. Methods and results The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alphaMHC-Cre(tg/-);gp130(fl/Y757F) [Y(757)F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y(757)F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y(757)F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by…
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Persistently activated STAT3 within cardiomyocytes results in a worse outcome following MI due, in part, to increased inflammation.
“However, persistently activated STAT3 within cardiomyocytes resulted in a worse outcome following MI due, in part, to increased inflammation (Hilfiker-Kleiner et al., 2010).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hilfiker-Kleiner et al., 2010
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Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration
Dierssen, U., Beraza, N., Lutz, H. H., Liedtke, C., Ernst, M., Wasmuth, H. E., & Trautwein, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m705483200 · Cited by 48 · see citing works
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“However, persistently activatedSTAT3within cardiomyocytes resulted in a worse outcome following MI due, in part, to increased inflammation (Hilfiker-Kleiner et al., 2010).”
BackgroundClearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery
Dookun, E., Walaszczyk, A., Redgrave, R., Palmowski, P., Tual‐Chalot, S., Suwana, A., Chapman, J., Jirkovsky, E., Donastorg Sosa, L., Gill, E., et al. (2020) · Aging Cell · doi:10.1111/acel.13249 · Cited by 173 · see citing works
- Authors
- Hilfiker-Kleiner, D., Shukla, P., Klein, G., Schaefer, A., Stapel, B., Hoch, M., Müller, W., Scherr, M., Theilmeier, G., Ernst, M., Hilfiker, A., & Drexler, H.
- Affiliations
- From the Departments of Cardiology and Angiology (D.H.-K., P.S., G.K., A.S., B.S., M.H., A.H.), Cardiac, Thoracic, Transplantation, and Vascular Surgery (A.H.), Haematology, Haemostaseology, Oncology, and Stem Cell Transplantation (M.S.), and Anesthesiology and Intensive Care Medicine (G.T.), Medical School Hannover, Hannover, Germany; Bill Ford Chair of Cellular Immunology, Faculty of Life Science, University of Manchester, Manchester, UK (W.M.); and Colon Molecular and Cell Biology Laboratory,...
- The Royal Melbourne Hospital (AU)
- ORCID
- Venue
- Circulation
- Published
- 2010-07-13
- Volume
- 122
- Issue
- 2
- Pages
- 145-155
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1978966324
- Cited by
- 167
- References
- 1
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 5 · 2023: 7 · 2022: 12 · 2021: 14 · 2020: 14 · 2019: 14 · 2018: 10 · 2017: 10 · 2016: 9 · 2015: 8 · 2014: 10 · 2013: 9 · 2012: 11
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- gp130, STAT3 activation, subacute myocardial infarction, interleukin-6, cardiac inflammation, left ventricular rupture, heart failure, complement activation, mannose-binding lectin, cobra venom factor, cardiomyocyte-specific knockout mice, cardiac remodeling, adverse outcomes, STAT3 inhibition
- MeSH terms
- Animals, Humans, Mice, Mutant Strains, Myocardial Infarction, Myocarditis, Rupture, Spontaneous, Down-Regulation, Interleukin-6, Mutation, Missense, Myocytes, Cardiac, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice
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