Brief murine myocardial I/R induces chemokines in a TNF-α-independent manner: Role of oxygen radicals

Tareck O. Nossuli, Nikolaos G. Frangogiannis, Pascal Knuefermann, Venkatesh Lakshminarayanan, Oliver Dewald, Alida J. Evans, Jacques Peschon, Douglas L. Mann, Lloyd H. Michael, Mark L. Entman

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Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-α, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-α-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-α double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1α, -1β, and -2 at both the mRNA and protein levels. This induction was independent of TNF-α, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-KB and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.

Original languageEnglish
Pages (from-to)H2549-H2558
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number6 50-6
StatePublished - 2001


  • Endothelium
  • Macrophage inflammatory protein
  • Transgenic animals


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