title: High-molecular-weight polyethylene glycol inhibits myocardial ischemia-reperfusion injury in vivo.
abstract: OBJECTIVE
  Cardiac ischemia-reperfusion (I-R) injury remains a significant 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 polyethylene glycol (PEG) (15-20 kD) can protect cardiac myocytes in vitro from hypoxia-reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo.
  
  
  METHODS
  Adult rats underwent left anterior descending artery occlusion for 60 minutes followed by 48 hours or 4 weeks of reperfusion. One milliliter of 10% PEG solution or phosphate-buffered saline (PBS) control (n = 10 per group) was administered intravenously (IV) immediately before reperfusion.
  
  
  RESULTS
  Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hour after IV delivery. The PEG group had significant recovery of left ventricular ejection fraction at 4 weeks versus a 25% decline in the PBS group (P < .01). There was 50% less LV fibrosis in the PEG group versus PBS with smaller peri-infarct and remote territory fibrosis (P < .01). Cell survival signaling was upregulated in the PEG group with increased Akt (3-fold, P < .01) and ERK (4-fold, P < .05) phosphorylation compared to PBS controls at 48 hours. PEG also inhibited apoptosis as measured by TUNEL-positive nuclei (56% decrease, P < .02) and caspase 3 activity (55% decrease, P < .05).
  
  
  CONCLUSIONS
  High-molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately before reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Xianyao
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Philip
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Md Abdur
authors.initials: MA
authors.lastname: Razzaque
authors.affiliation: University of Chicago Pritzker School of Medicine, Chicago, Ill.
authors.forename: James W
authors.initials: JW
authors.lastname: Lloyd
authors.affiliation: University of Chicago Pritzker School of Medicine, Chicago, Ill.
authors.forename: Charlie M
authors.initials: CM
authors.lastname: Muller
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wis. Electronic address: akhter@surgery.wisc.edu.
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Akhter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008970:Molecular Weight; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011092:Polyethylene Glycols; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3