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Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes

BACKGROUND: Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart....

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Autores principales: Ramírez, Elisa, Klett-Mingo, Mercedes, Ares-Carrasco, Sara, Picatoste, Belén, Ferrarini, Alessia, Rupérez, Francisco J, Caro-Vadillo, Alicia, Barbas, Coral, Egido, Jesús, Tuñón, José, Lorenzo, Óscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222723/
https://www.ncbi.nlm.nih.gov/pubmed/24261558
http://dx.doi.org/10.1186/1475-2840-12-172
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author Ramírez, Elisa
Klett-Mingo, Mercedes
Ares-Carrasco, Sara
Picatoste, Belén
Ferrarini, Alessia
Rupérez, Francisco J
Caro-Vadillo, Alicia
Barbas, Coral
Egido, Jesús
Tuñón, José
Lorenzo, Óscar
author_facet Ramírez, Elisa
Klett-Mingo, Mercedes
Ares-Carrasco, Sara
Picatoste, Belén
Ferrarini, Alessia
Rupérez, Francisco J
Caro-Vadillo, Alicia
Barbas, Coral
Egido, Jesús
Tuñón, José
Lorenzo, Óscar
author_sort Ramírez, Elisa
collection PubMed
description BACKGROUND: Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed. METHODS: Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells. RESULTS: In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone. CONCLUSIONS: By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats.
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spelling pubmed-42227232014-11-07 Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes Ramírez, Elisa Klett-Mingo, Mercedes Ares-Carrasco, Sara Picatoste, Belén Ferrarini, Alessia Rupérez, Francisco J Caro-Vadillo, Alicia Barbas, Coral Egido, Jesús Tuñón, José Lorenzo, Óscar Cardiovasc Diabetol Original Investigation BACKGROUND: Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed. METHODS: Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells. RESULTS: In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone. CONCLUSIONS: By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats. BioMed Central 2013-11-21 /pmc/articles/PMC4222723/ /pubmed/24261558 http://dx.doi.org/10.1186/1475-2840-12-172 Text en Copyright © 2013 Ramírez et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Investigation
Ramírez, Elisa
Klett-Mingo, Mercedes
Ares-Carrasco, Sara
Picatoste, Belén
Ferrarini, Alessia
Rupérez, Francisco J
Caro-Vadillo, Alicia
Barbas, Coral
Egido, Jesús
Tuñón, José
Lorenzo, Óscar
Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
title Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
title_full Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
title_fullStr Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
title_full_unstemmed Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
title_short Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
title_sort eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-ii diabetes
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222723/
https://www.ncbi.nlm.nih.gov/pubmed/24261558
http://dx.doi.org/10.1186/1475-2840-12-172
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