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Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation

Mudalagiri, NR; Mocanu, MM; Di Salvo, C; Kolvekar, S; Hayward, M; Yap, J; ... Yellon, DM; + view all (2008) Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation. BRIT J PHARMACOL , 153 (1) 50 - 56. 10.1038/sj.bjp.0707461. Gold open access

Abstract

Background and purposes: Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol-3 kinase (PI3K)/Akt and ERK1/2. However these pro-survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non-diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia-reoxygenation injury.Experimental approach: Human atrial trabeculae were exposed to 90min hypoxia and 120min reoxygenation. EPO was administered throughout reoxygenation. The developed force of contraction, calculated as a percentage of baseline force of contraction, was continuously monitored. The involvement of PI3K and ERK1/2 and the levels of activated caspase 3(AC3) were assessed.Key results: EPO improved the force of contraction in tissue from non-diabetic patients (46.7+/-1.7% vs. 30.2+/-2.2% in control, p < 0.001). These beneficial effects were prevented by the PI3K inhibitor, LY294002 and the ERK1/2 inhibitor, U0126. EPO also significantly improved the force of contraction in the diabetic tissue, although to a lesser degree. The levels of activated caspase 3 were significantly reduced in EPO treated trabeculae from both non-diabetic and diabetic patients, relative to their respective untreated controls.Conclusions and implications: EPO administered at reoxygenation protected human myocardial muscle by activating PI3K and ERK1/2 and reducing the level of activated caspase 3. This cardioprotection was also observed in the diabetic group. This data supports the potential of EPO being used as a novel cardioprotective strategy either alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.

Type:Article
Title:Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation
Open access status:An open access publication
DOI:10.1038/sj.bjp.0707461
Publisher version:http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC2199395/?tool=pubmed
Keywords:hypoxia, reoxygenation, signal transduction, diabetes, MAP kinase, PI3K/Akt, caspase 3, human myocardium, ISCHEMIA-REPERFUSION INJURY, SIGNAL-TRANSDUCTION, DEPENDENT PATHWAY, IN-VIVO, HEART, RATS, ISCHEMIA/REPERFUSION, PHOSPHORYLATION, INFARCTION, HYPOXIA
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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