Abstract 14049: High-Molecular-Weight Polyethylene Glycol (PEG) Inhibits Myocardial Ischemia-Reperfusion Injury and Improves Ventricular Function and Survival
Cardiac ischemia-reperfusion (I-R) injury remains a significant clinical problem as there are no therapies available to minimize the cell death that can lead to impaired function and heart failure. We have shown that high-molecular-weight PEG (15-20kD) can protect cardiac myocytes in vitro from hypoxia-reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo. Adult male rats underwent left thoracotomy and LAD occlusion for 60 minutes followed by either 48 hours (hrs) or 4 weeks (wks) of reperfusion. 1 mL of 10% PEG solution or saline (PBS) control (n=10 per group) was administered intravenously (IV) immediately prior to reperfusion. Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hr after IV delivery. Survival at 4 wks post-I-R was greater in the PEG group: 90% vs. 60% in PBS controls. The PEG group had full recovery of LV ejection fraction at 4 wks vs. 20% decline from baseline in the PBS group (p<0.03). There was 50% less LV fibrosis in the PEG group vs. PBS with significantly smaller peri-infarct and remote territory fibrosis (p<0.01). Cell survival signaling was upregulated in the PEG group with increased Akt (77% increase, p<0.002) and ERK (86% increase, p<0.05) phosphorylation compared to PBS controls at 48 hrs post-I-R injury. Consistent with increased Akt signaling, there was activation of downstream signaling targets as demonstrated by increased GSK 3β (4.3-fold, p=0.05) and eNOS (4.3-fold, p<0.02) phosphorylation in PEG vs. PBS. PEG inhibited apoptosis as measured by TUNEL positive nuclei (56% decrease, p<0.02) and caspase-3 activity (52% decrease, p<0.003) vs. PBS. High-molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately prior to reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery.
Author Disclosures: X. Xu: None. J.L. Philip: None. A. Razzaque: None. J.W. Lloyd: None. C.M. Muller: None. S.A. Akhter: None.
- © 2014 by American Heart Association, Inc.