| GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. | |
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MedLine Citation:
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PMID: 21516086 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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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Authors:
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Tibor Kempf; Alexander Zarbock; Christian Widera; Stefan Butz; Anika Stadtmann; Jan Rossaint; Matteo Bolomini-Vittori; Mortimer Korf-Klingebiel; L Christian Napp; Birte Hansen; Anna Kanwischer; Udo Bavendiek; Gernot Beutel; Martin Hapke; Martin G Sauer; Carlo Laudanna; Nancy Hogg; Dietmar Vestweber; Kai C Wollert |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-24 |
Journal Detail:
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Title: Nature medicine Volume: - ISSN: 1546-170X ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502015 Medline TA: Nat Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Hans Borst Center for Heart and Stem Cell Research, Hannover Medical School, Hannover, Germany. [2] Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. [3]. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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