Cargando…

Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils

Leukotrienes are among the most potent mediators of inflammation, and inhibition of their biosynthesis, is becoming increasingly important in the treatment of many pathologies. In this work, we demonstrated that preincubation of human neutrophils with the mitochondria targeted antioxidant SkQ1 (100 ...

Descripción completa

Detalles Bibliográficos
Autores principales: Sud’ina, Galina F., Golenkina, Ekaterina A., Prikhodko, Anastasia S., Kondratenko, Natalia D., Gaponova, Tatjana V., Chernyak, Boris V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729262/
https://www.ncbi.nlm.nih.gov/pubmed/36506526
http://dx.doi.org/10.3389/fphar.2022.1023517
_version_ 1784845450520559616
author Sud’ina, Galina F.
Golenkina, Ekaterina A.
Prikhodko, Anastasia S.
Kondratenko, Natalia D.
Gaponova, Tatjana V.
Chernyak, Boris V.
author_facet Sud’ina, Galina F.
Golenkina, Ekaterina A.
Prikhodko, Anastasia S.
Kondratenko, Natalia D.
Gaponova, Tatjana V.
Chernyak, Boris V.
author_sort Sud’ina, Galina F.
collection PubMed
description Leukotrienes are among the most potent mediators of inflammation, and inhibition of their biosynthesis, is becoming increasingly important in the treatment of many pathologies. In this work, we demonstrated that preincubation of human neutrophils with the mitochondria targeted antioxidant SkQ1 (100 nM) strongly inhibits leukotriene synthesis induced by three different stimuli: the Ca(2+) ionophore A23187, the chemotactic formyl-peptide fMLP in combination with cytocholasin B, and opsonized zymosan. The SkQ1 analogue lacking the antioxidant quinone moiety (C12TPP) was ineffective, suggesting that mitochondrial production of reactive oxygen species (ROS) is critical for activating of leukotriene synthesis in human neutrophils. The uncoupler of oxidative phosphorylation FCCP also inhibits leukotriene synthesis, indicating that a high membrane potential is a prerequisite for stimulating leukotriene synthesis in neutrophils. Our data show that activation of mitogen-activated protein kinases p38 and ERK1/2, which is important for leukotriene synthesis in neutrophils is a target for SkQ1: 1) the selective p38 inhibitor SB203580 inhibited fMLP-induced leukotriene synthesis, while the ERK1/2 activation inhibitor U0126 suppressed leukotriene synthesis induced by any of the three stimuli; 2) SkQ1 effectively prevents p38 and ERK1/2 activation (accumulation of phosphorylated forms) induced by all three stimuli. This is the first study pointing to the involvement of mitochondrial reactive oxygen species in the activation of leukotriene synthesis in human neutrophils. The use of mitochondria-targeted antioxidants can be considered as a promising strategy for inhibiting leukotriene synthesis and treating various inflammatory pathologies.
format Online
Article
Text
id pubmed-9729262
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-97292622022-12-09 Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils Sud’ina, Galina F. Golenkina, Ekaterina A. Prikhodko, Anastasia S. Kondratenko, Natalia D. Gaponova, Tatjana V. Chernyak, Boris V. Front Pharmacol Pharmacology Leukotrienes are among the most potent mediators of inflammation, and inhibition of their biosynthesis, is becoming increasingly important in the treatment of many pathologies. In this work, we demonstrated that preincubation of human neutrophils with the mitochondria targeted antioxidant SkQ1 (100 nM) strongly inhibits leukotriene synthesis induced by three different stimuli: the Ca(2+) ionophore A23187, the chemotactic formyl-peptide fMLP in combination with cytocholasin B, and opsonized zymosan. The SkQ1 analogue lacking the antioxidant quinone moiety (C12TPP) was ineffective, suggesting that mitochondrial production of reactive oxygen species (ROS) is critical for activating of leukotriene synthesis in human neutrophils. The uncoupler of oxidative phosphorylation FCCP also inhibits leukotriene synthesis, indicating that a high membrane potential is a prerequisite for stimulating leukotriene synthesis in neutrophils. Our data show that activation of mitogen-activated protein kinases p38 and ERK1/2, which is important for leukotriene synthesis in neutrophils is a target for SkQ1: 1) the selective p38 inhibitor SB203580 inhibited fMLP-induced leukotriene synthesis, while the ERK1/2 activation inhibitor U0126 suppressed leukotriene synthesis induced by any of the three stimuli; 2) SkQ1 effectively prevents p38 and ERK1/2 activation (accumulation of phosphorylated forms) induced by all three stimuli. This is the first study pointing to the involvement of mitochondrial reactive oxygen species in the activation of leukotriene synthesis in human neutrophils. The use of mitochondria-targeted antioxidants can be considered as a promising strategy for inhibiting leukotriene synthesis and treating various inflammatory pathologies. Frontiers Media S.A. 2022-11-24 /pmc/articles/PMC9729262/ /pubmed/36506526 http://dx.doi.org/10.3389/fphar.2022.1023517 Text en Copyright © 2022 Sud’ina, Golenkina, Prikhodko, Kondratenko, Gaponova and Chernyak. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sud’ina, Galina F.
Golenkina, Ekaterina A.
Prikhodko, Anastasia S.
Kondratenko, Natalia D.
Gaponova, Tatjana V.
Chernyak, Boris V.
Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils
title Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils
title_full Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils
title_fullStr Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils
title_full_unstemmed Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils
title_short Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils
title_sort mitochondria-targeted antioxidant skq1 inhibits leukotriene synthesis in human neutrophils
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729262/
https://www.ncbi.nlm.nih.gov/pubmed/36506526
http://dx.doi.org/10.3389/fphar.2022.1023517
work_keys_str_mv AT sudinagalinaf mitochondriatargetedantioxidantskq1inhibitsleukotrienesynthesisinhumanneutrophils
AT golenkinaekaterinaa mitochondriatargetedantioxidantskq1inhibitsleukotrienesynthesisinhumanneutrophils
AT prikhodkoanastasias mitochondriatargetedantioxidantskq1inhibitsleukotrienesynthesisinhumanneutrophils
AT kondratenkonataliad mitochondriatargetedantioxidantskq1inhibitsleukotrienesynthesisinhumanneutrophils
AT gaponovatatjanav mitochondriatargetedantioxidantskq1inhibitsleukotrienesynthesisinhumanneutrophils
AT chernyakborisv mitochondriatargetedantioxidantskq1inhibitsleukotrienesynthesisinhumanneutrophils