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The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway
PURPOSE: Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958154/ https://www.ncbi.nlm.nih.gov/pubmed/29582211 http://dx.doi.org/10.1007/s10557-018-6781-2 |
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author | Do Carmo, Helison Arjun, Sapna Petrucci, Orlando Yellon, Derek M Davidson, Sean M |
author_facet | Do Carmo, Helison Arjun, Sapna Petrucci, Orlando Yellon, Derek M Davidson, Sean M |
author_sort | Do Carmo, Helison |
collection | PubMed |
description | PURPOSE: Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC). METHODS: Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 μM VX-765, with precedent IPC, or the combination of VX-765 and IPC. RESULTS: VX-765 reduced infarct size (28 vs 48% control; P < 0.05) to a similar extent as IPC (30%; P < 0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC. CONCLUSIONS: The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection. |
format | Online Article Text |
id | pubmed-5958154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-59581542018-05-18 The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway Do Carmo, Helison Arjun, Sapna Petrucci, Orlando Yellon, Derek M Davidson, Sean M Cardiovasc Drugs Ther Short Communication PURPOSE: Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC). METHODS: Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 μM VX-765, with precedent IPC, or the combination of VX-765 and IPC. RESULTS: VX-765 reduced infarct size (28 vs 48% control; P < 0.05) to a similar extent as IPC (30%; P < 0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC. CONCLUSIONS: The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection. Springer US 2018-03-26 2018 /pmc/articles/PMC5958154/ /pubmed/29582211 http://dx.doi.org/10.1007/s10557-018-6781-2 Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Short Communication Do Carmo, Helison Arjun, Sapna Petrucci, Orlando Yellon, Derek M Davidson, Sean M The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway |
title | The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway |
title_full | The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway |
title_fullStr | The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway |
title_full_unstemmed | The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway |
title_short | The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway |
title_sort | caspase 1 inhibitor vx-765 protects the isolated rat heart via the risk pathway |
topic | Short Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958154/ https://www.ncbi.nlm.nih.gov/pubmed/29582211 http://dx.doi.org/10.1007/s10557-018-6781-2 |
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