title: 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.affiliation: Lund University, Mitochondrial Medicine and Department of Clinical Physiology and Nuclear Medicine, Clinical Sciences, 221 84 Lund, Sweden. Electronic address: Magnus.Hansson@med.lu.se.
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.affiliation: University of Bristol, School of Biochemistry and Bristol Cardio Vascular, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom. Electronic address: O.Llwyd@swansea.ac.uk.
authors.forename: Osian
authors.initials: O
authors.lastname: Llwyd
authors.affiliation: INSERM U955, Equipe 3, Université Paris Est, Faculté de Médecine, Créteil 94000, France. Electronic address: didier.morin@inserm.fr.
authors.forename: Didier
authors.initials: D
authors.lastname: Morin
authors.affiliation: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. Electronic address: damiendp@wanadoo.fr.
authors.forename: Damien
authors.initials: D
authors.lastname: de Paulis
authors.affiliation: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. Electronic address: arnouxthomas13@gmail.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnoux
authors.affiliation: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. Electronic address: cgouarne@trophos.com.
authors.forename: Caroline
authors.initials: C
authors.lastname: Gouarné
authors.affiliation: Lund University, Department of Cardiology, Clinical Sciences, 221 84 Lund, Sweden. Electronic address: sasha_koul@hotmail.com.
authors.forename: Sasha
authors.initials: S
authors.lastname: Koul
authors.affiliation: Lund University, Department of Clinical Physiology, Clinical Sciences, 221 84 Lund, Sweden. Electronic address: henrik.engblom@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Engblom
authors.affiliation: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. Electronic address: tbordet@gmail.com.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bordet
authors.affiliation: INSERM U955, Equipe 3, Université Paris Est, Faculté de Médecine, Créteil 94000, France. Electronic address: rtissier@vet-alfort.fr.
authors.forename: Renaud
authors.initials: R
authors.lastname: Tissier
authors.affiliation: Lund University, Department of Clinical Physiology, Clinical Sciences, 221 84 Lund, Sweden. Electronic address: hakan.arheden@med.lu.se.
authors.forename: Haakan
authors.initials: H
authors.lastname: Arheden
authors.affiliation: Lund University, Department of Cardiology, Clinical Sciences, 221 84 Lund, Sweden. Electronic address: david.erlinge@med.lu.se.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.affiliation: University of Bristol, School of Biochemistry and Bristol Cardio Vascular, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom. Electronic address: A.Halestrap@bristol.ac.uk.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Halestrap
authors.affiliation: INSERM U955, Equipe 3, Université Paris Est, Faculté de Médecine, Créteil 94000, France. Electronic address: alain.berdeaux@inserm.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.affiliation: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. Electronic address: rpruss@trophos.com.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
authors.affiliation: Trophos, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. Electronic address: sschaller@trophos.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Schaller
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control* / Q000628:therapy; D010091:Oximes / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012632:Secosteroids / Q000627:therapeutic use*; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D010091:Oximes; D017382:Reactive Oxygen Species; D012632:Secosteroids; C549911:3,5-seco-4-norcholestan-5-one oxime-3-ol
keywords: MitoQ (PubChem CID: 11388331); Mode of protection; Myocardial infarction; Reperfusion injury; TRO40303 (PubChem CID: 11524274)