eprintid: 10191937
rev_number: 7
eprint_status: archive
userid: 699
dir: disk0/10/19/19/37
datestamp: 2024-05-09 08:22:56
lastmod: 2024-05-09 08:22:56
status_changed: 2024-05-09 08:22:56
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Johnson, Thomas W
creators_name: Holt, James
creators_name: Kleyman, Anna
creators_name: Zhou, Shengyu
creators_name: Sammut, Eva
creators_name: Bruno, Vito Domenico
creators_name: Gaupp, Charlotte
creators_name: Stanzani, Giacomo
creators_name: Martin, John
creators_name: Arina, Pietro
creators_name: Deutsch, Julia
creators_name: Ascione, Raimondo
creators_name: Singer, Mervyn
creators_name: Dyson, Alex
title: Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G94
keywords: Mitochondria; Ischaemia; 
Reperfusion injury; Reactive oxygen species; 
Selenoprotein; Tetrathiomolybdate; 
Gasotransmitter
note: 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/).
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.
date: 2024-07
date_type: published
publisher: Elsevier BV
official_url: http://dx.doi.org/10.1016/j.redox.2024.103167
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2272871
doi: 10.1016/j.redox.2024.103167
medium: Print-Electronic
pii: S2213-2317(24)00143-5
lyricists_name: Singer, Mervyn
lyricists_id: MSING16
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Redox Biology
volume: 73
article_number: 103167
event_location: Netherlands
issn: 2213-2317
citation:        Johnson, Thomas W;    Holt, James;    Kleyman, Anna;    Zhou, Shengyu;    Sammut, Eva;    Bruno, Vito Domenico;    Gaupp, Charlotte;                             ... Dyson, Alex; + view all <#>        Johnson, Thomas W;  Holt, James;  Kleyman, Anna;  Zhou, Shengyu;  Sammut, Eva;  Bruno, Vito Domenico;  Gaupp, Charlotte;  Stanzani, Giacomo;  Martin, John;  Arina, Pietro;  Deutsch, Julia;  Ascione, Raimondo;  Singer, Mervyn;  Dyson, Alex;   - view fewer <#>    (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 <https://doi.org/10.1016/j.redox.2024.103167>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10191937/1/1-s2.0-S2213231724001435-main.pdf