Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation - the rat isolated working heart.

Abstract

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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 3 Pg. 633-47 (Feb 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 20942815 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Cardiotonic Agents
• Cyclic S-Oxides
• Guanidines
• Narcotic Antagonists
• Pyrazoles
• STAT3 Transcription Factor
• stattic
• Naloxone
• zoniporide
• L-Lactate Dehydrogenase
• Mitogen-Activated Protein Kinase 3
• Caspase 3

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Cardiovascular Physiological Phenomena (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)