Abstract 962: RAGE Mediates Maladaptive Remodeling in the Myocardium after Permanent Occlusion of the Left Anterior Descending Coronary Artery
The Receptor for Advanced Glycation Endproducts (RAGE) has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury; we previously reported that blockade of or homozygous deletion of RAGE conferred striking protection after transient occlusion/reperfusion of the left anterior descending (LAD) coronary artery. Here, we tested the role of RAGE after permanent occlusion of the LAD coronary artery. We subjected male homozygous RAGE null mice (RN, n=10) and their wild-type age-matched littermates (WT, n=10) to LAD occlusion and evaluated cardiac function before and 48hr, 7days 15 days and one month after infarction. Significant improvement in fractional shortening was observed in RN animals (31±4.8% vs. 13.4±4.1% 1 week after infarction and 27.8±3.4% vs. 18±4.0% one month after, p<0.05), as assessed by echocardiography. Scar formation, based on Masson’s trichrome staining, was significantly decreased in RN vs. wild-type mice 1 month after infarction (27±3.2% vs. 38±4%); p<0.05. In parallel, diastolic diameter was increased by 16% in RAGE−/− vs. WT hearts at one month after infarction; p<0.05. Consistent with key roles for RAGE in mechanisms linked to injury, significantly increased expression of RAGE was demonstrated in the peri-infarction zone 48 hrs after infarct vs. baseline myocardium without infarction. Cells were prominently expressing RAGE after infarction included endothelial cells > smooth muscle > and cardiomyocyte itself in diminishing pattern. Taken together, these data indicate that RAGE amplifies injury in the peri-infarct period; deletion of RAGE conferred significantly improved functional recovery and scarring of the myocardium after injury. These data indicate that RAGE blockade may limit sustained injury in the myocardium, even beyond the period of frank infarction.