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Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart

The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) male animals develop obesity and type 2 diabetes. Morbidity and mortality from cardiovascular complications, due to increased oxidative stress and inflammatory signals, are the hallmarks of type 2 diabetes. The pr...

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Autores principales: Raza, Haider, John, Annie, Howarth, Frank C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546687/
https://www.ncbi.nlm.nih.gov/pubmed/23203193
http://dx.doi.org/10.3390/ijms131216241
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author Raza, Haider
John, Annie
Howarth, Frank C.
author_facet Raza, Haider
John, Annie
Howarth, Frank C.
author_sort Raza, Haider
collection PubMed
description The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) male animals develop obesity and type 2 diabetes. Morbidity and mortality from cardiovascular complications, due to increased oxidative stress and inflammatory signals, are the hallmarks of type 2 diabetes. The precise molecular mechanism of contractile dysfunction and disease progression remains to be clarified. Therefore, we have investigated molecular and metabolic targets in male ZDF (30–34 weeks old) rat heart compared to age matched Zucker lean (ZL) controls. Hyperglycemia was confirmed by a 4-fold elevation in non-fasting blood glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22 ± 2.52 mg/dL in ZL rats). An increase in reactive oxygen species production, lipid peroxidation and oxidative protein carbonylation was observed in ZDF rats. A significant increase in CYP4502E1 activity accompanied by increased protein expression was also observed in diabetic rat heart. Increased expression of other oxidative stress marker proteins, HO-1 and iNOS was also observed. GSH concentration and activities of GSH-dependent enzymes, glutathione S-transferase and GSH reductase, were, however, significantly increased in ZDF heart tissue suggesting a compensatory defense mechanism. The activities of mitochondrial respiratory enzymes, Complex I and Complex IV were significantly reduced in the heart ventricle of ZDF rats in comparison to ZL rats. Western blot analysis has also suggested a decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results have suggested that mitochondrial dysfunction and increased oxidative stress in ZDF rats might be associated, at least in part, with altered NF-κB/JNK dependent redox cell signaling. These results might have implications in the elucidation of the mechanism of disease progression and designing strategies for diabetes prevention.
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spelling pubmed-35466872013-01-23 Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart Raza, Haider John, Annie Howarth, Frank C. Int J Mol Sci Article The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) male animals develop obesity and type 2 diabetes. Morbidity and mortality from cardiovascular complications, due to increased oxidative stress and inflammatory signals, are the hallmarks of type 2 diabetes. The precise molecular mechanism of contractile dysfunction and disease progression remains to be clarified. Therefore, we have investigated molecular and metabolic targets in male ZDF (30–34 weeks old) rat heart compared to age matched Zucker lean (ZL) controls. Hyperglycemia was confirmed by a 4-fold elevation in non-fasting blood glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22 ± 2.52 mg/dL in ZL rats). An increase in reactive oxygen species production, lipid peroxidation and oxidative protein carbonylation was observed in ZDF rats. A significant increase in CYP4502E1 activity accompanied by increased protein expression was also observed in diabetic rat heart. Increased expression of other oxidative stress marker proteins, HO-1 and iNOS was also observed. GSH concentration and activities of GSH-dependent enzymes, glutathione S-transferase and GSH reductase, were, however, significantly increased in ZDF heart tissue suggesting a compensatory defense mechanism. The activities of mitochondrial respiratory enzymes, Complex I and Complex IV were significantly reduced in the heart ventricle of ZDF rats in comparison to ZL rats. Western blot analysis has also suggested a decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results have suggested that mitochondrial dysfunction and increased oxidative stress in ZDF rats might be associated, at least in part, with altered NF-κB/JNK dependent redox cell signaling. These results might have implications in the elucidation of the mechanism of disease progression and designing strategies for diabetes prevention. Molecular Diversity Preservation International (MDPI) 2012-11-30 /pmc/articles/PMC3546687/ /pubmed/23203193 http://dx.doi.org/10.3390/ijms131216241 Text en © 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0 This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Raza, Haider
John, Annie
Howarth, Frank C.
Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart
title Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart
title_full Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart
title_fullStr Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart
title_full_unstemmed Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart
title_short Alterations in Glutathione Redox Metabolism, Oxidative Stress, and Mitochondrial Function in the Left Ventricle of Elderly Zucker Diabetic Fatty Rat Heart
title_sort alterations in glutathione redox metabolism, oxidative stress, and mitochondrial function in the left ventricle of elderly zucker diabetic fatty rat heart
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546687/
https://www.ncbi.nlm.nih.gov/pubmed/23203193
http://dx.doi.org/10.3390/ijms131216241
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