Opposing Effects Mediated by the Chemokine Receptor CXCR2 on Myocardial Ischemia-Reperfusion Injury: Recruitment of Potentially Damaging Neutrophils and Direct Myocardial Protection

Sima T. Tarzami, Wenfeng Miao, Kartik Mani, Lillie Lopez, Stephen M. Factor, Joan W. Berman, Richard N. Kitsis

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Background - The timely reperfusion of ischemic myocardium limits infarction, but components of reperfusion, such as inflammation, may be injurious. The chemokine receptor CXCR2 mediates neutrophil chemotaxis. CXCR2 activation also inhibits hypoxia-induced death of isolated cardiac myocytes. This study assesses whether CXCR2 mediates protection in the intact heart and, if so, the magnitude of this protection relative to CXCR2-mediated chemotaxis of potentially damaging inflammatory cells. Methods and Results - After ischemia-reperfusion in vivo, CXCR2-/- mice exhibited infarcts that were 50.5% smaller (P<0.05) with 44.3% fewer inflammatory cells (P<0.05) than wild type mice. These data suggest that in this model, CXCR2-mediated chemotaxis may be important in myocardial cell death. To isolate the role of CXCR2 specifically on blood cells, adoptive transfer experiments were performed. After ischemia-reperfusion, infarcts were 53.4% smaller (P<0.05) and contained 65.0% fewer inflammatory cells (P<0.05) in lethally irradiated wild type mice reconstituted with CXCR2-/- compared with wild type bone marrow. Thus, CXCR2 on blood cells is important in myocardial damage, most likely because of CXCR2-mediated chemotaxis. To unmask whether CXCR2 mediates direct myocardial protection in the intact heart, wild type and CXCR2 -/- hearts were studied in the absence of blood using Langendorff preparations. In this case, infarcts were 19.7% larger in CXCR2-/- than wild type hearts (P<0.05), revealing a novel CXCR2-mediated cardioprotective effect. Conclusions - CXCR2 exerts opposing effects on myocardial viability during ischemia-reperfusion with recruitment of damaging inflammatory cells predominant over direct tissue protection.

Original languageEnglish (US)
Pages (from-to)2387-2392
Number of pages6
JournalCirculation
Volume108
Issue number19
DOIs
StatePublished - Nov 11 2003

Keywords

  • Chemokines
  • Ischemia
  • Leukocytes
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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