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Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol‐3 kinase and ERK1/2 activation
Author(s) -
Mudalagiri N R,
Mocanu M M,
Di Salvo C,
Kolvekar S,
Hayward M,
Yap J,
Keogh B,
Yellon D M
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707461
Subject(s) - cardioprotection , medicine , erythropoietin , hypoxia (environmental) , ly294002 , pi3k/akt/mtor pathway , myocardial infarction , contraction (grammar) , cardiology , pharmacology , apoptosis , chemistry , oxygen , biochemistry , organic chemistry
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. British Journal of Pharmacology (2008) 153 , 50–56; doi: 10.1038/sj.bjp.0707461 ; published online 22 October 2007