RAGE Contributes to Aldose Reductase mediated myocardial ischemia‐reperfusion Injury

Abstract

The efficacy of reperfusion therapy in limiting infarction and improving recovery of contractile function depends on the amount of irreversible damage occurring prior to initiating reperfusion. In this context, our earlier studies demonstrated that the activity of myocardial aldose reductase (AR) (a key regulatory enzyme in polyol pathway) is increased during ischemia and that inhibition of AR protected ischemic myocardium. Mechanisms by which increased AR mediates ischemia‐reperfusion (IR) injury is evolving. We have hypothesized that AR contributes to generation of advanced glycation end product (AGE) precursors, thereby facilitating the interaction of AGEs with its receptor (RAGE) and subsequent signaling for cellular injury in myocardial infarction. To determine the contribution of AR pathway towards generation of key AGE precursors, 3‐deoxyglucosone (3‐DG) and methylglyoxal (MG), we measured myocardial levels of 3‐DG and MG in Wild type (WT), and human AR expressing (hARTg) transgenic mice. To determine if AR modulates IR injury via increases in AGE‐RAGE interaction, we performed LAD occlusion (30 min) followed by 48 hours of reperfusion in WT, hARTg, RAGE knockout (RKO), RAGE knockout bred into hARTg background (AR‐RKO) mice hearts. 3‐DG and MG levels were significantly greater in hAR Tg hearts than in WT (p<0.05), with corresponding increases in AGE levels and RAGE transcripts. Infarct area was significantly greater and functional recovery was poor in the hARTg mice compared to WT mice hearts (p<0.05). Significant reduction in infarct area was observed in ARI treated hARTg, RKO, and AR‐RKO vs WT mice hearts (p<0.05). These data indicate that genetic deletion of RAGE reduces infarct area in hARTg and WT mice hearts, and that AR mediates IR injury via RAGE‐dependent and RAGE‐independent pathways.