@article{discovery10191937,
           month = {July},
          volume = {73},
            note = {Crown Copyright {\copyright} 2024 Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/bync/4.0/).},
            year = {2024},
           title = {Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion},
       publisher = {Elsevier BV},
         journal = {Redox Biology},
            issn = {2213-2317},
          author = {Johnson, Thomas W and Holt, James and Kleyman, Anna and Zhou, Shengyu and Sammut, Eva and Bruno, Vito Domenico and Gaupp, Charlotte and Stanzani, Giacomo and Martin, John and Arina, Pietro and Deutsch, Julia and Ascione, Raimondo and Singer, Mervyn and Dyson, Alex},
        abstract = {Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p {\ensuremath{<}} 0.05). Blood troponin T levels were significantly (p {\ensuremath{<}} 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p {\ensuremath{<}} 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.},
             url = {http://dx.doi.org/10.1016/j.redox.2024.103167},
        keywords = {Mitochondria; Ischaemia; 
Reperfusion injury; Reactive oxygen species; 
Selenoprotein; Tetrathiomolybdate; 
Gasotransmitter}
}