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PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS
Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Epoxyeicosatrienoic acids (EETs) are biologically active metabolites of arachidonic acids capable of activating protective cellular pathway...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227494/ https://www.ncbi.nlm.nih.gov/pubmed/25426073 http://dx.doi.org/10.3389/fphar.2014.00242 |
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author | Samokhvalov, Victor Vriend, Jelle Jamieson, Kristi L. Akhnokh, Maria K. Manne, Rajkumar Falck, John R. Seubert, John M. |
author_facet | Samokhvalov, Victor Vriend, Jelle Jamieson, Kristi L. Akhnokh, Maria K. Manne, Rajkumar Falck, John R. Seubert, John M. |
author_sort | Samokhvalov, Victor |
collection | PubMed |
description | Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Epoxyeicosatrienoic acids (EETs) are biologically active metabolites of arachidonic acids capable of activating protective cellular pathways in response to stress stimuli. EETs evoke a plethora of pathways limiting impairments of cellular structures, reducing cell death, and promoting anti-inflammatory reactions in various cell types. Considering EETs are capable of producing various biological protective effects, we hypothesized that EETs would protect rat neonatal cardiomyocytes (NCM) against LPS-induced cytotoxicity. In this study, we used a dual-acting, synthetic analog of EETs, UA-8 [13-(3-propylureido)tridec-8-enoic acid], possessing both EET-mimetic and soluble epoxide hydrolase selective inhibitory properties and 14,15-EET as a model of canonical EET molecules. We found that both UA-8 and 14,15-EET significantly improved cell viability and mitochondrial function of cardiomyocytes exposed to LPS. Furthermore, treatment with UA-8 or 14,15-EET resulted in significant attenuation of LPS-triggered pro-inflammatory response, caspase-3 activation and reduction in the total antioxidant capacity in cardiomyocytes. Importantly, EET-mediated effects were significantly reduced by pharmacological inhibition of peroxisome proliferator-activated receptors γ (PPARγ) suggesting that PPARγ signaling was required for EETs exerted protective effects. Data presented in the current study demonstrate that activation of PPARγ signaling plays a crucial role in EET-mediated protection against LPS-cytotoxicity in cardiomyocytes. |
format | Online Article Text |
id | pubmed-4227494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-42274942014-11-25 PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS Samokhvalov, Victor Vriend, Jelle Jamieson, Kristi L. Akhnokh, Maria K. Manne, Rajkumar Falck, John R. Seubert, John M. Front Pharmacol Pharmacology Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Epoxyeicosatrienoic acids (EETs) are biologically active metabolites of arachidonic acids capable of activating protective cellular pathways in response to stress stimuli. EETs evoke a plethora of pathways limiting impairments of cellular structures, reducing cell death, and promoting anti-inflammatory reactions in various cell types. Considering EETs are capable of producing various biological protective effects, we hypothesized that EETs would protect rat neonatal cardiomyocytes (NCM) against LPS-induced cytotoxicity. In this study, we used a dual-acting, synthetic analog of EETs, UA-8 [13-(3-propylureido)tridec-8-enoic acid], possessing both EET-mimetic and soluble epoxide hydrolase selective inhibitory properties and 14,15-EET as a model of canonical EET molecules. We found that both UA-8 and 14,15-EET significantly improved cell viability and mitochondrial function of cardiomyocytes exposed to LPS. Furthermore, treatment with UA-8 or 14,15-EET resulted in significant attenuation of LPS-triggered pro-inflammatory response, caspase-3 activation and reduction in the total antioxidant capacity in cardiomyocytes. Importantly, EET-mediated effects were significantly reduced by pharmacological inhibition of peroxisome proliferator-activated receptors γ (PPARγ) suggesting that PPARγ signaling was required for EETs exerted protective effects. Data presented in the current study demonstrate that activation of PPARγ signaling plays a crucial role in EET-mediated protection against LPS-cytotoxicity in cardiomyocytes. Frontiers Media S.A. 2014-11-11 /pmc/articles/PMC4227494/ /pubmed/25426073 http://dx.doi.org/10.3389/fphar.2014.00242 Text en Copyright © 2014 Samokhvalov, Vriend, Jamieson, Akhnokh, Manne, Falck and Seubert. http://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) or licensor 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 Samokhvalov, Victor Vriend, Jelle Jamieson, Kristi L. Akhnokh, Maria K. Manne, Rajkumar Falck, John R. Seubert, John M. PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS |
title | PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS |
title_full | PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS |
title_fullStr | PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS |
title_full_unstemmed | PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS |
title_short | PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS |
title_sort | pparγ signaling is required for mediating eets protective effects in neonatal cardiomyocytes exposed to lps |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227494/ https://www.ncbi.nlm.nih.gov/pubmed/25426073 http://dx.doi.org/10.3389/fphar.2014.00242 |
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