Editors' ChoiceCardiac Physiology

PEG Gets to the Heart of the Matter

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Science Translational Medicine  30 Mar 2011:
Vol. 3, Issue 76, pp. 76ec45
DOI: 10.1126/scitranslmed.3002427

Although it will never be featured as the “perp” in an episode of Law and Order, ischemia is a serial killer—of cells, organs, people. The condition, which occurs during stroke and heart disease, is caused by a block in blood flow and thus in the delivery of essentials—including oxygen—to organs. The ischemic condition triggers a cascade of biochemical events in cells that begins a switch to anaerobic metabolism and ends with breakdown of mitochondria and cell death. To make matters worse, when blood flow is restored (reperfusion), many viable cells will often become suicidal. This apoptotic pathway that is activated by cardiac ischemia-reperfusion injury represents a prime target for therapies that can preserve cardiac cells and thus prevent heart failure. Malhorta and colleagues now demonstrate that the polymer polyethylene glycol (PEG) has a potent, protective antiapoptotic effect on cardiac myocytes exposed to ischemia-reperfusion injury.

First, the authors showed that cultured cardiac myocytes that had been pretreated with 5% PEG undergo significantly less apoptosis compared with untreated controls when subjected to oxygen deprivation. This effect was mediated through preservation of mitochondrial membranes—as measured by a decrease in the release of the mitochondrial protein cytochrome c and a subsequent reduction in caspase-3 activity, an enzyme that incites apoptosis. Furthermore, when oxygen was restored to the PEG-treated cells to simulate ischemia-reperfusion, the authors measured a significant reduction in reactive oxygen species (ROS) relative to cells not treated with PEG. In addition to preventing apoptosis, Malhorta and colleagues showed that signaling through several cell-survival pathways was up-regulated—specifically, the Akt-glycogen synthase kinase-3β (GSK-3β) and mitogen-activated protein kinase kinase/extracellular signal–regulated kinase (ERK) pathways, which regulate cell metabolism, growth, and division. To corroborate these in vitro experiments, the authors used an ex vivo Langendorff perfusion model, which uses an isolated heart in a perfused system to study physiological responses. Pretreatment of rat hearts with PEG or buffered saline followed by 3 hours of ischemia at 4°C (cold ischemia) and then reperfusion with standard solution at normothermic conditions preserved function in the left ventricule of the heart. In the absense of PEG treatment, there was an increase in apoptosis and a significant reduction in overall cardiac function—specifically, left-ventricular systolic and diastolic functions. These observations suggest that the beneficial effects of PEG on cardiac myocyte survival in vitro translate to improved heart function ex vivo.

PEG has been used clinically for cold-ischemia heart preservation in the transplantation setting. The new study identifies a role for PEG in ischemia-reperfusion injury and a potential mechanism for PEG-related improvement in cardiac function. In this drama, researchers rather than the police are closing in on a serial killer.

R. Malhotra et al. High molecular weight polyethylene glycol protects cardiac myocytes from hypoxia and reoxygention-induced cell death and preserves ventricular function. Am. J. Physiol. Heart Circ. Physiol. 18 February 2011 (10.1152/ajpheart.01054.2010). [PubMed]

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