title: Thrombopoietin receptor agonists protect human cardiac myocytes from injury by activation of cell survival pathways.
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.
authors.affiliation: Division of Cardiothoracic Surgery (J.E.B., J.S., S.K.), Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Department of Emergency Medicine (T.P.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Biotechnology, Anna University, Chennai, India (A.D.) jbaker@mcw.edu.
authors.forename: John E
authors.initials: JE
authors.lastname: Baker
authors.affiliation: Division of Cardiothoracic Surgery (J.E.B., J.S., S.K.), Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Department of Emergency Medicine (T.P.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Biotechnology, Anna University, Chennai, India (A.D.).
authors.forename: Jidong
authors.initials: J
authors.lastname: Su
authors.affiliation: Division of Cardiothoracic Surgery (J.E.B., J.S., S.K.), Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Department of Emergency Medicine (T.P.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Biotechnology, Anna University, Chennai, India (A.D.).
authors.forename: Stacy
authors.initials: S
authors.lastname: Koprowski
authors.affiliation: Division of Cardiothoracic Surgery (J.E.B., J.S., S.K.), Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Department of Emergency Medicine (T.P.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Biotechnology, Anna University, Chennai, India (A.D.).
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dhanasekaran
authors.affiliation: Division of Cardiothoracic Surgery (J.E.B., J.S., S.K.), Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Department of Emergency Medicine (T.P.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Biotechnology, Anna University, Chennai, India (A.D.).
authors.forename: Tom P
authors.initials: TP
authors.lastname: Aufderheide
authors.affiliation: Division of Cardiothoracic Surgery (J.E.B., J.S., S.K.), Department of Pharmacology and Toxicology (J.E.B., G.J.G.), Department of Emergency Medicine (T.P.A.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Center for Biotechnology, Anna University, Chennai, India (A.D.).
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013926:Thrombopoietin / Q000494:pharmacology
chemical_list: D001565:Benzoates; D002316:Cardiotonic Agents; D006834:Hydrazines; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin; C520809:eltrombopag