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Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice

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Abstract

Acute hyperglycemia during acute myocardial infarction is associated with worse myocardial injury and increased mortality. Using a mouse model of myocardial ischemia/reperfusion injury, we tested the hypothesis that acute hyperglycemia activates splenic leukocytes and subsequently exacerbates myocardial infarct size. We then examined whether the adverse effects of hyperglycemia could be attenuated by a potent anti-inflammatory agent (an agonist of the adenosine A2A receptor) administered immediately prior to reperfusion. C57BL6 (WT) mice underwent 30-min LAD occlusion and 60-min reperfusion with or without prior splenectomy. Acute hyperglycemia before ischemia increased myocardial infarct size (IS) by 43 % (p < 0.05). Splenectomy before ischemia did not change IS (vs. control, p = NS) but did serve to prevent the exacerbation of IS by hyperglycemia. Acute hyperglycemia activated splenic leukocytes by increasing formyl peptide receptor expression and reactive oxygen species production before ischemia, and enhanced splenic neutrophil release with resultant peripheral neutrophilia and increased myocardial neutrophil infiltration during reperfusion. Acute adoptive transfer of splenic leukocytes to splenectomized mice before ischemia restored the hyperglycemic exacerbation of infarct size. ATL146e, an adenosine 2A receptor (A2AR) agonist, abolished neutrophilia during reperfusion and reduced IS in hyperglycemic mice. ATL146e also reduced IS in splenectomized hyperglycemic mice with transfer of WT splenic leukocytes, but not with transfer of splenic leukocytes from A2AR knockout mice. Acute hyperglycemia prior to myocardial ischemia and reperfusion exacerbates IS by activating splenic leukocytes. ATL146e administered at reperfusion suffices to abrogate the hyperglycemic exacerbation of IS by acting on A2ARs on splenic leukocytes.

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Acknowledgments

This study was funded in part by University of Virginia Department of Surgery Startup Funds and University of Virginia School of Medicine Collaborative Science Pilot Grant to ZY and by NIH R01 HL 092305 to ILK and BAF.

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Authors and Affiliations

  1. Departments of Surgery, University of Virginia, PO Box 800709, Charlottesville, VA, 22908, USA

    Yikui Tian, Irving L. Kron & Zequan Yang

  2. Biomedical Engineering, University of Virginia, Charlottesville, VA, USA

    Brent A. French & Zequan Yang

  3. Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA

    Brent A. French

  4. Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China

    Yikui Tian

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Tian, Y., French, B.A., Kron, I.L. et al. Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice. Basic Res Cardiol 110, 39 (2015). https://doi.org/10.1007/s00395-015-0496-3

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