Abstract 15706: Increased Cardiac Expression of the Receptor for Advanced Glycation End Products is Associated With Myocardial Apoptosis in Patients Post Coronary Artery Bypass Grafting and in Mice Following Myocardial Infarction
Introduction: On-pump coronary artery bypass graft (CABG) surgery often induces a systemic inflammatory response leading to myocardial injury and additional cardiomyocyte apoptosis. The receptor for advanced glycation end products (RAGE) is upregulated in key injuries to the heart, including ischemia/reperfusion injury, and inflammation.
Hypothesis: Recent data suggests a possible correlation between RAGE with the degree of post CABG myocardial injury.
Methods: : In this study we examined RAGE mRNA and protein and indeces of apoptosis in atrial tissue from 59 patients (45 male) age 64.6±1.0 (years) taken before aortic occlusion and after reperfusion post CABG. To identify the functional importance of RAGE in myocardial injury, 12 week old RAGE knockout (KO) mice underwent coronary artery ligation to produce acute myocardial infarction (AMI).
Results: Serum sRAGE and atrial RAGE (mRNA and protein) increased 15-35% post CABG. Markers of atrial apoptosis, caspase-3 activity, BAX/BCL2 ratio, and TUNEL positive myocyte nuclei increased 25-45% post CABG. There was a positive correlation (r=0.370, p=0.004) between atrial RAGE and pro-apoptotic BAX mRNAs. We compared 19 wild-type (WT), 34 RAGE KO mice over 35 days following AMI with sham-operated controls. Of those, 7/19 WT-, and 2/34 RAGE KO-infarcted and 0/28 sham-operated mice died during the observation period. Compared to sham, RAGE mRNA and protein increased 3-4 fold in WT following AMI. Among survivors, postmortem examination indicated that the WT compared to RAGE KO infarcted mice had increased left ventricular apoptosis as quantified by 3.5 fold increase in caspase-3 activity, 5.2 fold increase in BAX/BCL2 ratio and augmented % TUNEL positive myocyte nuclei -WT 4.35±0.52 vs. 2.18±0.31 , p<0.05). The post infarct end-diastolic pressure was lower in RAGE KO than in WT mice (9.5±1.1 vs. 13.9±1.5, mmHg p<0.05, respectively).
Conclusions: Our data suggests increased RAGE expression is associated with myocardial apoptosis in post CABG patients and WT mice following AMI. Since RAGE KO compared to WT mice demonstrated a structural, functional and survival advantage, RAGE could be a novel therapeutic target in the management of apoptosis.
Author Disclosures: J. Tsoporis: None. J. Desjardins: None. S. Izhar: None. V. Salpeas: None. I.K. Rizos: None. T.G. Parker: None.
- © 2016 by American Heart Association, Inc.