title: Thyroid hormone improves postischaemic recovery of function while limiting apoptosis: a new therapeutic approach to support hemodynamics in the setting of ischaemia-reperfusion?
abstract: Although it has long been recognized that thyroid hormone is an effective positive inotrope, its efficacy in supporting hemodynamics in the acute setting of ischaemia and reperfusion (R) without worsening reperfusion injury remains largely unknown. Thus, we investigated the effects of triiodothyronine (T3) on reperfusion injury in a Langendorff-perfused rat heart model of 30 min zero-flow ischaemia and 60 min of (R) with or without T3 (40 microg/l) at R, T3-R60, n = 11 and CNT-R60, n = 10, respectively. Furthermore, phosphorylated levels of intracellular kinases were measured at 5, 15 and 60 min of R. T3 markedly improved postischaemic recovery of left ventricular developed pressure (LVDP%); 56.0% (SEM, 4.4) in T3-R60 versus 38.8% (3.1) in CNT-R60, P < 0.05. Furthermore, LDH release was significantly lower in T3-R60. Apoptosis detection by fluorescent probe optical imaging showed increased fluorescent signal in CNT-R60 hearts, while the signal was hardly detectable in T3-R60 hearts. Similarly, caspase-3 activity was found to be 78.2 (8.2) in CNT-R60 vs 40.5 (7.1) in T3-R60 hearts, P < 0.05. This response was associated with significantly lower levels of phospho-p38 MAPK at any time point of R. No significant changes in phospho- ERK1/2 and JNK levels were observed between groups. Phospho-Akt levels were significantly lower in T3 treated group at 5 min and no change in phospho-Akt levels were observed at 15 and 60 min between groups. In conclusion, T3 administration at reperfusion can improve postischaemic recovery of function while limiting apoptosis. This may constitute a paradigm of a positive inotropic agent with anti-apoptotic action suitable for supporting hemodynamics in the clinical setting of ischaemia-reperfusion.
authors.affiliation: Department of Pharmacology, University of Athens, 75 Mikras Asias Ave., Goudi, Athens, Greece. cpantos@cc.uoa.gr
authors.forename: Constantinos
authors.initials: C
authors.lastname: Pantos
authors.forename: Iordanis
authors.initials: I
authors.lastname: Mourouzis
authors.forename: Theodosios
authors.initials: T
authors.lastname: Saranteas
authors.forename: Guillaume
authors.initials: G
authors.lastname: Clavé
authors.forename: Heidi
authors.initials: H
authors.lastname: Ligeret
authors.forename: Pauline
authors.initials: P
authors.lastname: Noack-Fraissignes
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
authors.forename: Marc
authors.initials: M
authors.lastname: Massonneau
authors.forename: Philipos
authors.initials: P
authors.lastname: Perimenis
authors.forename: Danai
authors.initials: D
authors.lastname: Spanou
authors.forename: Georgia
authors.initials: G
authors.lastname: Kostopanagiotou
authors.forename: Dennis V
authors.initials: DV
authors.lastname: Cokkinos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001696:Biomechanical Phenomena; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014284:Triiodothyronine / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D011506:Proteins; D014284:Triiodothyronine; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3