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Thrombopoietin receptor agonists protect human cardiac myocytes from injury by activation of cell survival pathways. J Pharmacol Exp Ther 2015 Mar;352(3):429-37

Date

12/17/2014

Pubmed ID

25512369

DOI

10.1124/jpet.114.221747

Scopus ID

2-s2.0-84921466193   6 Citations

Abstract

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart. Eltrombopag is a small molecule agonist of the thrombopoietin receptor, the physiologic target of thrombopoietin. However, the ability of eltrombopag and thrombopoietin to protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (n = 6-10/group) were treated with eltrombopag (0.1-30.0 µM) or thrombopoietin (0.1-30.0 ng/ml) and then subjected to 5 hours of hypoxia (95% N2/5% CO2) and 16 hours of reoxygenation to determine their ability to confer resistance to myocardial injury. The thrombopoietin receptor c-Mpl was detected in unstimulated human cardiac myocytes by Western blotting. Eltrombopag and thrombopoietin confer immediate protection to human cardiac myocytes against injury from hypoxia/reoxygenation by decreasing necrotic and apoptotic cell death in a concentration-dependent manner, with an optimal concentration of 3 µM for eltrombopag and 1.0 ng/ml for thrombopoietin. The extent of protection conferred with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple prosurvival pathways; inhibition of Janus kinase-2, proto-oncogene tyrosine-protein kinase, protein kinase B/phosphatidylinositol-3 kinase, p44/42 mitogen-activated protein kinase (MAPK), and p38 MAPK abolished cardiac myocyte protection by eltrombopag and thrombopoietin. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer a long-lasting benefit through activation of prosurvival pathways during ischemia.

Author List

Baker JE, Su J, Koprowski S, Dhanasekaran A, Aufderheide TP, Gross GJ

Authors

Tom P. Aufderheide MD Professor in the Emergency Medicine department at Medical College of Wisconsin
John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Benzoates
Cardiotonic Agents
Cell Hypoxia
Cell Survival
Cells, Cultured
Dose-Response Relationship, Drug
Humans
Hydrazines
Myocytes, Cardiac
Pyrazoles
Receptors, Thrombopoietin
Signal Transduction
Thrombopoietin
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a