Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades
Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protect...
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doaj-a34aadafea8446e585c0ab3f5e044bf62020-11-25T03:54:36ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942020-01-01202010.1155/2020/92198259219825Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox CascadesClaudia Penna0Manuela Aragno1Alessia Sofia Cento2Saveria Femminò3Isabella Russo4Federica Dal Bello5Fausto Chiazza6Debora Collotta7Gustavo Ferreira Alves8Massimo Bertinaria9Elisa Zicola10Valentina Mercurio11Claudio Medana12Massimo Collino13Pasquale Pagliaro14Department of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Translational Medical Sciences, Federico II University, Naples, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyInhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol. The selective NLRP3 inflammasome inhibitor INF (50 μM) was infused before the IR protocol to the hearts from untreated animals or pretreated with Ticagrelor. In parallel experiments, the hearts isolated from untreated animals were perfused with Ticagrelor (3.70 μM) before ischemia and subjected to IR. The hearts of animals pretreated with Ticagrelor showed a significantly reduced infarct size (IS, 49±3% of area at risk, AAR) when compared to control IR group (69±2% of AAR). Similarly, ex vivo administration of INF before the IR injury resulted in significant IS reduction (38±3% of AAR). Myocardial IR induced the NLRP3 inflammasome complex formation, which was attenuated by either INF pretreatment ex vivo, or by repeated oral treatment with Ticagrelor. The beneficial effects induced by either treatment were associated with the protective Reperfusion Injury Salvage Kinase (RISK) pathway activation and redox defence upregulation. In contrast, no protective effects nor NLRP3/RISK modulation were recorded when Ticagrelor was administered before ischemia in isolated heart, indicating that Ticagrelor direct target is not in the myocardium. Our results confirm that Ticagrelor conditioning effects are likely mediated through platelets, but are not additives to the ones achieved by directly inhibiting NLRP3.http://dx.doi.org/10.1155/2020/9219825 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Claudia Penna Manuela Aragno Alessia Sofia Cento Saveria Femminò Isabella Russo Federica Dal Bello Fausto Chiazza Debora Collotta Gustavo Ferreira Alves Massimo Bertinaria Elisa Zicola Valentina Mercurio Claudio Medana Massimo Collino Pasquale Pagliaro |
spellingShingle |
Claudia Penna Manuela Aragno Alessia Sofia Cento Saveria Femminò Isabella Russo Federica Dal Bello Fausto Chiazza Debora Collotta Gustavo Ferreira Alves Massimo Bertinaria Elisa Zicola Valentina Mercurio Claudio Medana Massimo Collino Pasquale Pagliaro Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades Oxidative Medicine and Cellular Longevity |
author_facet |
Claudia Penna Manuela Aragno Alessia Sofia Cento Saveria Femminò Isabella Russo Federica Dal Bello Fausto Chiazza Debora Collotta Gustavo Ferreira Alves Massimo Bertinaria Elisa Zicola Valentina Mercurio Claudio Medana Massimo Collino Pasquale Pagliaro |
author_sort |
Claudia Penna |
title |
Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades |
title_short |
Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades |
title_full |
Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades |
title_fullStr |
Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades |
title_full_unstemmed |
Ticagrelor Conditioning Effects Are Not Additive to Cardioprotection Induced by Direct NLRP3 Inflammasome Inhibition: Role of RISK, NLRP3, and Redox Cascades |
title_sort |
ticagrelor conditioning effects are not additive to cardioprotection induced by direct nlrp3 inflammasome inhibition: role of risk, nlrp3, and redox cascades |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2020-01-01 |
description |
Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol. The selective NLRP3 inflammasome inhibitor INF (50 μM) was infused before the IR protocol to the hearts from untreated animals or pretreated with Ticagrelor. In parallel experiments, the hearts isolated from untreated animals were perfused with Ticagrelor (3.70 μM) before ischemia and subjected to IR. The hearts of animals pretreated with Ticagrelor showed a significantly reduced infarct size (IS, 49±3% of area at risk, AAR) when compared to control IR group (69±2% of AAR). Similarly, ex vivo administration of INF before the IR injury resulted in significant IS reduction (38±3% of AAR). Myocardial IR induced the NLRP3 inflammasome complex formation, which was attenuated by either INF pretreatment ex vivo, or by repeated oral treatment with Ticagrelor. The beneficial effects induced by either treatment were associated with the protective Reperfusion Injury Salvage Kinase (RISK) pathway activation and redox defence upregulation. In contrast, no protective effects nor NLRP3/RISK modulation were recorded when Ticagrelor was administered before ischemia in isolated heart, indicating that Ticagrelor direct target is not in the myocardium. Our results confirm that Ticagrelor conditioning effects are likely mediated through platelets, but are not additives to the ones achieved by directly inhibiting NLRP3. |
url |
http://dx.doi.org/10.1155/2020/9219825 |
work_keys_str_mv |
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