TY  - JOUR
TI  - Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion
Y1  - 2024/07//
AV  - public
VL  - 73
N1  - 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/).
N2  - 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.
ID  - discovery10191937
UR  - http://dx.doi.org/10.1016/j.redox.2024.103167
PB  - Elsevier BV
SN  - 2213-2317
JF  - Redox Biology
A1  - Johnson, Thomas W
A1  - Holt, James
A1  - Kleyman, Anna
A1  - Zhou, Shengyu
A1  - Sammut, Eva
A1  - Bruno, Vito Domenico
A1  - Gaupp, Charlotte
A1  - Stanzani, Giacomo
A1  - Martin, John
A1  - Arina, Pietro
A1  - Deutsch, Julia
A1  - Ascione, Raimondo
A1  - Singer, Mervyn
A1  - Dyson, Alex
KW  - Mitochondria; Ischaemia; 
Reperfusion injury; Reactive oxygen species; 
Selenoprotein; Tetrathiomolybdate; 
Gasotransmitter
ER  -