Abstract 12580: Acute Hyperglycemia Exacerbates Myocardial Infarct Size by Activating NKT Cells - An Effect that can be Abrogated by Adenosine 2A Receptor Activation at Reperfusion
Introduction: Multiple clinical trials show that acute hyperglycemia during myocardial infarction (MI) is associated with larger MIs and increased mortality. We hypothesized that acute hyperglycemia exacerbates MI by activating NKT cells. If so, it follows that an anti-inflammatory agent might suffice to abrogate the adverse effects of hyperglycemia on MI.
Methods: C57BL6 (WT) mice and congenic knockout (KO) mice were assigned to 9 groups that underwent MI surgery in which the LAD was ligated for 30 min followed by 60 min of reperfusion. Hyperglycemia was induced by ip injection of 2 g/kg Dextrose (20%) 30 min before LAD occlusion. ATL133, an A2AR agonist, was injected iv at 10 μg/kg in ATL-treated mice 5 min before reperfusion. MI size (IF) and risk region (RR) were determined by TTC and Phthalo blue staining, respectively.
Results: Acute hyperglycemic (HG) mice had significantly higher plasma glucose levels compared to euglycemic mice (420±28 vs. 165±6 g/dl). In WT mice, HG increased IF by 44% from 34.0±2.7 to 48.8±1.6% RR (see Fig). ATL133 significantly reduced IF in WT mice (22.6±3.7 vs. 34.0±2.7% RR) and completely abolished the hyperglycemic exacerbation of IF (25.7±3.6 vs. 48.8±1.6% RR). Our previous work showed that the infarct-sparing effect of A2AR agonists is primarily due to their effect on CD4+ T cells. We then tested the HG effect in immunodeficient mice and found that acute HG did not exacerbate IF in RAG1 KO (12.8±1.4 vs. 18.7±3.2%RR with HG) or Jα18 KO mice which lack NKT cells (15.3±3.3 vs. 24.5±2.0% RR with HG). Furthermore, iv injection of 200μg of CD1d-specific mAb 24h before surgery completely abrogated the hyperglycemic exacerbation of IF (24.1±4.8 in HG+CD1d depletion vs. 48.8±1.6% RR in WT+HG).
Conclusion: Acute hyperglycemia during MI exacerbates IF size by activating NKT cells, likely through CD1d. Administration of an A2AR agonist just prior to reperfusion suffices to abrogate the hyperglycemic exacerbation of IF, likely through its action on NKT cells.
- © 2013 by American Heart Association, Inc.