Differences in the profile of protection afforded by TRO40303 and mild hypothermia in models of cardiac ischemia/reperfusion injury.

Abstract

The mode of protection against cardiac reperfusion injury by mild hypothermia and TRO40303 was investigated in various experimental models and compared to MitoQ in vitro. In isolated cardiomyocytes subjected to hypoxia/reoxygenation, TRO40303, MitoQ and mild hypothermia delayed mPTP opening, inhibited generation of mitochondrial superoxide anions at reoxygenation and improved cell survival. Mild hypothermia, but not MitoQ and TRO40303, provided protection in a metabolic starvation model in H9c2 cells and preserved respiratory function in isolated rat heart mitochondria submitted to anoxia/reoxygenation. In the Langendorff-perfused rat heart, only mild hypothermia provided protection of hemodynamic function and reduced infarct size following ischemia/reperfusion. In biopsies from the left ventricle of pigs subjected to in vivo occlusion/reperfusion, TRO40303 specifically preserved respiratory functions in the peri-infarct zone whereas mild hypothermia preserved both the ischemic core area and the peri-infarct zones. Additionally in this pig model, only hypothermia reduced infarct size. We conclude that mild hypothermia provided protection in all models by reducing the detrimental effects of ischemia, and when initiated before occlusion, reduced subsequent reperfusion damage leading to a smaller infarct. By contrast, although TRO40303 provided similar protection to MitoQ in vitro and offered specific protection against some aspects of reperfusion injury in vivo, this was insufficient to reduce infarct size.

• Authors: Magnus J Hansson, Osian Llwyd, Didier Morin, Damien de Paulis, Thomas Arnoux, Caroline Gouarné, Sasha Koul, Henrik Engblom, Thierry Bordet, Renaud Tissier, Haakan Arheden, David Erlinge, Andrew P Halestrap, Alain Berdeaux, Rebecca M Pruss, Sophie Schaller
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 760 Pg. 7-19 (Aug 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 25895640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Cardiotonic Agents
• Oximes
• Reactive Oxygen Species
• Secosteroids
• 3,5-seco-4-norcholestan-5-one oxime-3-ol

Topics

• Animals
• Cardiotonic Agents (therapeutic use)
• Cells, Cultured
• Female
• Hypothermia, Induced (methods)
• Male
• Myocardial Reperfusion Injury (metabolism, prevention & control, therapy)
• Oximes (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Secosteroids (therapeutic use)
• Swine