Cardioprotective Effect of ‘Methylamine Irisolidone’, a New Compound, in Hypoxia/Reoxygenation Injury in Cultured Rat Cardiac Myocytes

2009 ◽  
Vol 6 (8) ◽  
pp. 1170-1177 ◽  
Author(s):  
Yan-Ling Mu ◽  
Yan-Ying Xie ◽  
Ling Zhou ◽  
Ying Zhong ◽  
Lu Liu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardioprotective Effect ◽  
Reoxygenation Injury ◽  
Rat Cardiac Myocytes ◽  
Hypoxia Reoxygenation

Abstract 172: Thrombopoietin Receptor Agonists Protect Human Cardiac Myocytes from Injury by Activation of Cell Survival Pathways

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
John E Baker ◽  
Jidong Su ◽  
Stacy Koprowski ◽  
Anuradha Dhanasekaran ◽  
Tom P Aufderheide ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Survival Pathways ◽  
Thrombopoietin Receptor ◽  
Reoxygenation Injury ◽  
Hypoxia Reoxygenation

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart at a dose that does not increase platelet levels. Eltrombopag is a small molecule agonist of the thrombopoietin receptor; the physiological target of thrombopoietin. Administration of thrombopoietin and eltrombopag result in a dose- and time-dependent increase in platelet counts in patients with thrombocytopenia. However, the ability of eltrombopag and thrombopoietin to immediately protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (7500 cells, n=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% N 2 /5%CO 2 ) and 16 hours of reoxygenation to determine their ability to confer resistance to necrotic and apoptotic 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 to cardiac myocytes with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple pro-survival pathways; inhibition of JAK-2 (AG-490, 10 μM), p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 10 μM), Akt/PI 3 kinase (Wortmannin, 100 nM), and src kinase (PP1, 20 μM) prior to and during hypoxia abolished cardiac myocyte protection by eltrombopag and thrombopoietin. These inhibitors had no effect on hypoxia/reoxygenation injury in myocytes when used alone. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer long-lasting benefit through activation of pro-survival pathways during ischemia.

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