title: AP39, a mitochondria-targeting hydrogen sulfide (H2S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling.
abstract: H2S protects myocardium against ischaemia/reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of a mitochondria-specific H2S donor, AP39, at reperfusion against ischaemia/reperfusion injury.
  
  
  
  Anaesthetized rats underwent myocardial ischaemia (30 min)/reperfusion (120 min) with randomization to receive interventions before reperfusion: vehicle, AP39 (0.01, 0.1, 1 μmol·kg-1), or control compounds AP219 and ADT-OH (1 μmol·kg-1). LY294002, L-NAME or ODQ were used to investigate the involvement of the RISK pathway. Myocardial samples harvested 5 min after reperfusion were analysed for RISK protein phosphorylation and isolated cardiac mitochondria were used to examine the direct mitochondrial effects of AP39.
  
  
  
  AP39, dose-dependently, reduced infarct size. Inhibition of either PI3K/Akt, eNOS or sGC did not affect this effect of AP39. Western blot analysis confirmed that AP39 did not induce phosphorylation of Akt, eNOS, GSK-3β or ERK1/2. In isolated subsarcolemmal and interfibrillar mitochondria, AP39 significantly attenuated mitochondrial ROS generation without affecting respiratory complexes I or II. Furthermore, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co-incubation of mitochondria with AP39 and cyclosporine A induced an additive inhibitory effect on the PTP.
  
  
  
  AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. This cardioprotective effect could be mediated by inhibiting PTP via a cyclophilin D-independent mechanism. Thus, selective delivery of H2S to mitochondria may be therapeutically applicable for employing the cardioprotective utility of H2S.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.|College of Medicine, University of Diyala, Diyala, Iraq.
authors.forename: Qutuba G
authors.identifier: 0000-0003-2897-6630
authors.initials: QG
authors.lastname: Karwi
authors.affiliation: Institute of Physiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bornbaum
authors.affiliation: Institute of Physiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Boengler
authors.affiliation: Medical School, University of Exeter, Exeter, UK.|School of Biosciences, University of Exeter, Exeter, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Torregrossa
authors.affiliation: Medical School, University of Exeter, Exeter, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: School of Biosciences, University of Exeter, Exeter, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: Institute of Physiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Baxter
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013871:Thiones / Q000494:pharmacology*
chemical_list: C000610725:AP39 compound; D009943:Organophosphorus Compounds; D047428:Protein Kinase Inhibitors; D013871:Thiones; D011494:Protein Kinases