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Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation

BACKGROUND: Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ische...

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Autores principales: Aguiar, Carla J, Rocha-Franco, João A, Sousa, Pedro A, Santos, Anderson K, Ladeira, Marina, Rocha-Resende, Cibele, Ladeira, Luiz O, Resende, Rodrigo R, Botoni, Fernando A, Barrouin Melo, Marcos, Lima, Cristiano X, Carballido, José M, Cunha, Thiago M, Menezes, Gustavo B, Guatimosim, Silvia, Leite, M Fatima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296677/
https://www.ncbi.nlm.nih.gov/pubmed/25539979
http://dx.doi.org/10.1186/s12964-014-0078-2
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author Aguiar, Carla J
Rocha-Franco, João A
Sousa, Pedro A
Santos, Anderson K
Ladeira, Marina
Rocha-Resende, Cibele
Ladeira, Luiz O
Resende, Rodrigo R
Botoni, Fernando A
Barrouin Melo, Marcos
Lima, Cristiano X
Carballido, José M
Cunha, Thiago M
Menezes, Gustavo B
Guatimosim, Silvia
Leite, M Fatima
author_facet Aguiar, Carla J
Rocha-Franco, João A
Sousa, Pedro A
Santos, Anderson K
Ladeira, Marina
Rocha-Resende, Cibele
Ladeira, Luiz O
Resende, Rodrigo R
Botoni, Fernando A
Barrouin Melo, Marcos
Lima, Cristiano X
Carballido, José M
Cunha, Thiago M
Menezes, Gustavo B
Guatimosim, Silvia
Leite, M Fatima
author_sort Aguiar, Carla J
collection PubMed
description BACKGROUND: Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ischemia increase succinate blood levels, we investigated the role of this metabolite during a heart ischemic event, using human and rodent models. RESULTS: We found that succinate causes cardiac hypertrophy in a GPR91 dependent manner. GPR91 activation triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), the expression of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm, which are hypertrophic-signaling events. Furthermore, we found that serum levels of succinate are increased in patients with cardiac hypertrophy associated with acute and chronic ischemic diseases. CONCLUSIONS: These results show for the first time that succinate plays an important role in cardiomyocyte hypertrophy through GPR91 activation, and extend our understanding of how ischemia can induce hypertrophic cardiomyopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-014-0078-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-42966772015-01-17 Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation Aguiar, Carla J Rocha-Franco, João A Sousa, Pedro A Santos, Anderson K Ladeira, Marina Rocha-Resende, Cibele Ladeira, Luiz O Resende, Rodrigo R Botoni, Fernando A Barrouin Melo, Marcos Lima, Cristiano X Carballido, José M Cunha, Thiago M Menezes, Gustavo B Guatimosim, Silvia Leite, M Fatima Cell Commun Signal Research BACKGROUND: Succinate is an intermediate of the citric acid cycle as well as an extracellular circulating molecule, whose receptor, G protein-coupled receptor-91 (GPR91), was recently identified and characterized in several tissues, including heart. Because some pathological conditions such as ischemia increase succinate blood levels, we investigated the role of this metabolite during a heart ischemic event, using human and rodent models. RESULTS: We found that succinate causes cardiac hypertrophy in a GPR91 dependent manner. GPR91 activation triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), the expression of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and the translocation of histone deacetylase 5 (HDAC5) into the cytoplasm, which are hypertrophic-signaling events. Furthermore, we found that serum levels of succinate are increased in patients with cardiac hypertrophy associated with acute and chronic ischemic diseases. CONCLUSIONS: These results show for the first time that succinate plays an important role in cardiomyocyte hypertrophy through GPR91 activation, and extend our understanding of how ischemia can induce hypertrophic cardiomyopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-014-0078-2) contains supplementary material, which is available to authorized users. BioMed Central 2014-12-24 /pmc/articles/PMC4296677/ /pubmed/25539979 http://dx.doi.org/10.1186/s12964-014-0078-2 Text en © Aguiar et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Aguiar, Carla J
Rocha-Franco, João A
Sousa, Pedro A
Santos, Anderson K
Ladeira, Marina
Rocha-Resende, Cibele
Ladeira, Luiz O
Resende, Rodrigo R
Botoni, Fernando A
Barrouin Melo, Marcos
Lima, Cristiano X
Carballido, José M
Cunha, Thiago M
Menezes, Gustavo B
Guatimosim, Silvia
Leite, M Fatima
Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
title Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
title_full Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
title_fullStr Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
title_full_unstemmed Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
title_short Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation
title_sort succinate causes pathological cardiomyocyte hypertrophy through gpr91 activation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296677/
https://www.ncbi.nlm.nih.gov/pubmed/25539979
http://dx.doi.org/10.1186/s12964-014-0078-2
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