Document Detail


Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation - the rat isolated working heart.
MedLine Citation:
PMID:  20942815     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Ischemia-reperfusion injury plays an important role in the development of primary allograft failure after heart transplantation. Inhibition of the Na+/H+ exchanger is one of the most promising therapeutic strategies for treating ischemia-reperfusion injury. Here we have characterized the cardioprotective efficacy of zoniporide and the underlying mechanisms in a model of myocardial preservation using rat isolated working hearts.
EXPERIMENTAL APPROACH: Rat isolated hearts subjected to 6 h hypothermic (1-4°C) storage followed by 45 min reperfusion at 37°C were treated with zoniporide at different concentrations and timing. Recovery of cardiac function, levels of total and phosphorylated protein kinase B, extracellular signal-regulated kinase 1/2, glycogen synthase kinase-3β and STAT3 as well as cleaved caspase 3 were measured at the end of reperfusion. Lactate dehydrogenase release into coronary effluent before and post-storage was also measured.
KEY RESULTS: Zoniporide concentration-dependently improved recovery of cardiac function after reperfusion. The functional recovery induced by zoniporide was accompanied by up-regulation of p-extracellular signal-regulated kinase 1/2 and p-STAT3, and by reduction in lactate dehydrogenase release and cleaved caspase 3. There were no significant differences in any of the above indices when zoniporide was administered before, during or after ischemia. The STAT3 inhibitor, stattic, abolished zoniporide-induced improvements in functional recovery and up-regulation of p-STAT3 after reperfusion.
CONCLUSIONS AND IMPLICATIONS: Zoniporide is a potent cardioprotective agent and activation of STAT3 plays a critical role in the cardioprotective action of zoniporide. This agent shows promise as a supplement to storage solutions to improve preservation of donor hearts.
Authors:
L Gao; J Tsun; L Sun; J Kwan; A Watson; P S Macdonald; M Hicks
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  162     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-13     Completed Date:  2011-07-26     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  633-47     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiotonic Agents / pharmacology*
Cardiovascular Physiological Processes / drug effects*
Caspase 3 / metabolism
Cyclic S-Oxides / metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Guanidines / pharmacology*
Heart / physiology
Heart Transplantation*
L-Lactate Dehydrogenase / metabolism
Male
Mitogen-Activated Protein Kinase 3 / metabolism
Myocardium / metabolism
Naloxone / metabolism
Narcotic Antagonists / metabolism
Pyrazoles / pharmacology*
Rats
Rats, Wistar
Reperfusion Injury / drug therapy*,  prevention & control*
STAT3 Transcription Factor / antagonists & inhibitors,  metabolism*
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Cyclic S-Oxides; 0/Guanidines; 0/Narcotic Antagonists; 0/Pyrazoles; 0/STAT3 Transcription Factor; 0/stattic; 465-65-6/Naloxone; 8841R2UJPG/zoniporide; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 3.4.22.-/Caspase 3
Comments/Corrections

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