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

Nature Medicine, ISSN: 1078-8956, Vol: 17, Issue: 5, Page: 581-588
2011
  • 420
    Citations
  • 0
    Usage
  • 294
    Captures
  • 4
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    420
  • Captures
    294
  • Mentions
    4
    • News Mentions
      3
      • News
        3
    • References
      1
      • Wikipedia
        1

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Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease

Introduction Chronic kidney disease (CKD) has garnered global attention due to its prevalence, progressive nature, and irreversibility. The renal function of patients with CKD continues

Article Description

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 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 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. © 2011 Nature America, Inc. All rights reserved.

Bibliographic Details

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

Springer Science and Business Media LLC

Biochemistry, Genetics and Molecular Biology

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