Abstract 12485: Myocardial Infarct Exacerbation by Acute Hyperglycemia is Mediated Through a RAGE Independent Mechanism
Introduction: Acute hyperglycemia during myocardial infarction (MI) is associated with higher clinical mortality and increased infarct size in the mouse model of reperfused MI. Chronic hyperglycemia is known to activate the Receptor for Advanced Glycation Endproducts (RAGE) through formation of AGE, and RAGE is a known mediator of ischemia/reperfusion injury. We hypothesized that acute hyperglycemic exacerbation of MI might be mediated through RAGE signaling.
Methods: Reperfused MI was performed on wild-type B6 mice (n=18) and congenic RAGE KO mice (n=16) treated with either dextrose (20%, 10ml/kg, IP) or saline (10ml/kg, IP) 20 min before coronary occlusion. MI consisted of 30 min coronary occlusion followed by 2 h of reperfusion. Infarct size as percent area at risk (IF%) was determined by planimetry after TTC and Phthalo blue staining.
Results: Acute hyperglycemia exacerbates MI similarly in both WT mice (16% increase, 47±5% vs. 63±3%, p=0.01) and RAGE KO mice (22% increase, 31±5% vs. 53±4%, p<0.01). IF% in RAGE KO mice was reduced by 16% compared to WT mice under euglycemic conditions (31± 5% vs. 47±5%, p= 0.04) and by 10% under hyperglycemic conditions (53±4% vs. 63±3%, p=0.05). The area at risk for all groups are similar (p=NS).
Conclusions: Acute hyperglycemia causes a similar increase in infarct size regardless of presence of RAGE, while RAGE KO causes a similar reduction in infarct size regardless of glycemic status. Thus, the adverse effects of hyperglycemia and RAGE on MI appear to work through independent mechanisms. Furthermore, these results predict that therapies aimed at reducing infarct size through the inhibition of RAGE signaling will be beneficial both in normoglycemic and hyperglycemic patients.
- © 2011 by American Heart Association, Inc.