title: Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice.
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.
authors.affiliation: Departments of Surgery, University of Virginia, PO Box 800709, Charlottesville, VA, 22908, USA.
authors.forename: Yikui
authors.initials: Y
authors.lastname: Tian
authors.forename: Brent A
authors.initials: BA
authors.lastname: French
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Zequan
authors.initials: Z
authors.lastname: Yang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D006943:Hyperglycemia / Q000209:etiology*; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications*; D009504:Neutrophils / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000502:physiology; D013154:Spleen / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D043705:Receptor, Adenosine A2A