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Cited by 523GDF15 and Related BiomarkersCardiac Fibrosis and RemodelingCardiac Ischemia and Reperfusion

The DOI matches its Crossref record; 52 of the 53 references it cites were found in a registry or an index.

GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice

Kempf, Tibor, Zarbock, Alexander, Widera, Christian, Butz, Stefan, Stadtmann, Anika, Rossaint, Jan, Bolomini-Vittori, Matteo, Korf-Klingebiel, Mortimer, Napp, L Christian, Hansen, Birte, Kanwischer, Anna, Bavendiek, Udo, Beutel, Gernot, Hapke, Martin, Sauer, Martin G, Laudanna, Carlo, Hogg, Nancy, Vestweber, Dietmar, Wollert, Kai C·2011·Nature Medicine
DOI 10.1038/nm.2354
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Abstract

Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-β (TGF-β)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of β(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of β(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.

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Research works printed but not linked: 6

  1. Hsiao, E.C. et al. Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol. Cell. Biol. 20, 3742–3751 (2000). · DOI · Paper page
  2. Kempf, T. et al. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ. Res. 98, 351–360 (2006). · DOI · Paper page
  3. Matsumura, S. et al. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J. Clin. Invest. 115, 599–609 (2005). · DOI
  4. Bolomini-Vittori, M. et al. Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module. Nat. Immunol. 10, 185–194 (2009). · DOI
  5. Dransfield, I. & Hogg, N. Regulated expression of Mg2+ binding epitope on leukocyte integrin α subunits. EMBO J. 8, 3759–3765 (1989). · DOI
  6. Lum, A.F., Green, C.E., Lee, G.R., Staunton, D.E. & Simon, S.I. Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow. J. Biol. Chem. 277, 20660–20670 (2002). · DOI

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Metadata

Authors
Kempf, T., Zarbock, A., Widera, C., Butz, S., Stadtmann, A., Rossaint, J., Bolomini-Vittori, M., Korf-Klingebiel, M., Napp, L. C., Hansen, B., Kanwischer, A., Bavendiek, U., Beutel, G., Hapke, M., Sauer, M. G., Laudanna, C., Hogg, N., Vestweber, D., & Wollert, K. C.
Affiliations
  • Medizinische Hochschule Hannover (DE)
  • University of Münster (DE)
  • University of Verona (IT)
  • Cancer Research UK (GB)
Corresponding author
  • Vestweber, Dietmar
  • Wollert, Kai C
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2011-04-24
Volume
17
Issue
5
Pages
581-588
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2354
OpenAlex
W2010044292
Cited by
518
References
53
Citations by year
2026: 21 · 2025: 30 · 2024: 50 · 2023: 32 · 2022: 38 · 2021: 32 · 2020: 52 · 2019: 27 · 2018: 29 · 2017: 31 · 2016: 33 · 2015: 42 · 2014: 32 · 2013: 29 · 2012: 29
FWCI
23.53
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
Keywords
GDF15, myocardial infarction, leukocyte recruitment, beta2 integrins, leukocyte transmigration, polymorphonuclear leukocytes, cardiac rupture, Cdc42, Rap1, chemokine signaling, anti-inflammatory cytokines, leukocyte adhesion, transendothelial migration, myeloid cells
MeSH terms
Animals, Cell Adhesion, Cell Movement, Male, Mice, Inbred C57BL, Myocardial Infarction, Neutrophils, Signal Transduction, Integrins, Mice, Knockout, CD18 Antigens, cdc42 GTP-Binding Protein, rap1 GTP-Binding Proteins, Myeloid Cells, Mice, Growth Differentiation Factor 15, Mice, 129 Strain

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