Johnson, Thomas W;
Holt, James;
Kleyman, Anna;
Zhou, Shengyu;
Sammut, Eva;
Bruno, Vito Domenico;
Gaupp, Charlotte;
... Dyson, Alex; + view all
(2024)
Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion.
Redox Biology
, 73
, Article 103167. 10.1016/j.redox.2024.103167.
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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 < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 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.
| Type: | Article |
|---|---|
| Title: | Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.redox.2024.103167 |
| Publisher version: | http://dx.doi.org/10.1016/j.redox.2024.103167 |
| Language: | English |
| Additional information: | Crown 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/). |
| Keywords: | Mitochondria; Ischaemia; Reperfusion injury; Reactive oxygen species; Selenoprotein; Tetrathiomolybdate; Gasotransmitter |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10191937 |
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