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Insulin signaling alters antioxidant capacity in the diabetic heart
Diabetic cardiomyopathy is associated with an increase in oxidative stress. However, antioxidant therapy has shown a limited capacity to mitigate disease pathology. The molecular mechanisms responsible for the modulation of reactive oxygen species (ROS) production and clearance must be better define...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473541/ https://www.ncbi.nlm.nih.gov/pubmed/34560411 http://dx.doi.org/10.1016/j.redox.2021.102140 |
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author | Matsuzaki, Satoshi Eyster, Craig Newhardt, Maria F. Giorgione, Jennifer R. Kinter, Caroline Young, Zachary T. Kinter, Michael Humphries, Kenneth M. |
author_facet | Matsuzaki, Satoshi Eyster, Craig Newhardt, Maria F. Giorgione, Jennifer R. Kinter, Caroline Young, Zachary T. Kinter, Michael Humphries, Kenneth M. |
author_sort | Matsuzaki, Satoshi |
collection | PubMed |
description | Diabetic cardiomyopathy is associated with an increase in oxidative stress. However, antioxidant therapy has shown a limited capacity to mitigate disease pathology. The molecular mechanisms responsible for the modulation of reactive oxygen species (ROS) production and clearance must be better defined. The objective of this study was to determine how insulin affects superoxide radical (O(2)(•–)) levels. O(2)(•–) production was evaluated in adult cardiomyocytes isolated from control and Akita (type 1 diabetic) mice by spin-trapping electron paramagnetic resonance spectroscopy. We found that the basal rates of O(2)(•–) production were comparable in control and Akita cardiomyocytes. However, culturing cardiomyocytes without insulin resulted in a significant increase in O(2)(•–) production only in the Akita group. In contrast, O(2)(•–) production was unaffected by high glucose and/or fatty acid supplementation. The increase in O(2)(•–) was due in part to a decrease in superoxide dismutase (SOD) activity. The PI3K inhibitor, LY294002, decreased Akita SOD activity when insulin was present, indicating that the modulation of antioxidant activity is through insulin signaling. The effect of insulin on mitochondrial O(2)(•–) production was evaluated in Akita mice that underwent a 1-week treatment of insulin. Mitochondria isolated from insulin-treated Akita mice produced less O(2)(•–) than vehicle-treated diabetic mice. Quantitative proteomics was performed on whole heart homogenates to determine how insulin affects antioxidant protein expression. Of 29 antioxidant enzymes quantified, thioredoxin 1 was the only one that was significantly enhanced by insulin treatment. In vitro analysis of thioredoxin 1 revealed a previously undescribed capacity of the enzyme to directly scavenge O(2)(•–). These findings demonstrate that insulin has a role in mitigating cardiac oxidative stress in diabetes via regulation of endogenous antioxidant activity. |
format | Online Article Text |
id | pubmed-8473541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84735412021-10-01 Insulin signaling alters antioxidant capacity in the diabetic heart Matsuzaki, Satoshi Eyster, Craig Newhardt, Maria F. Giorgione, Jennifer R. Kinter, Caroline Young, Zachary T. Kinter, Michael Humphries, Kenneth M. Redox Biol Short Communication Diabetic cardiomyopathy is associated with an increase in oxidative stress. However, antioxidant therapy has shown a limited capacity to mitigate disease pathology. The molecular mechanisms responsible for the modulation of reactive oxygen species (ROS) production and clearance must be better defined. The objective of this study was to determine how insulin affects superoxide radical (O(2)(•–)) levels. O(2)(•–) production was evaluated in adult cardiomyocytes isolated from control and Akita (type 1 diabetic) mice by spin-trapping electron paramagnetic resonance spectroscopy. We found that the basal rates of O(2)(•–) production were comparable in control and Akita cardiomyocytes. However, culturing cardiomyocytes without insulin resulted in a significant increase in O(2)(•–) production only in the Akita group. In contrast, O(2)(•–) production was unaffected by high glucose and/or fatty acid supplementation. The increase in O(2)(•–) was due in part to a decrease in superoxide dismutase (SOD) activity. The PI3K inhibitor, LY294002, decreased Akita SOD activity when insulin was present, indicating that the modulation of antioxidant activity is through insulin signaling. The effect of insulin on mitochondrial O(2)(•–) production was evaluated in Akita mice that underwent a 1-week treatment of insulin. Mitochondria isolated from insulin-treated Akita mice produced less O(2)(•–) than vehicle-treated diabetic mice. Quantitative proteomics was performed on whole heart homogenates to determine how insulin affects antioxidant protein expression. Of 29 antioxidant enzymes quantified, thioredoxin 1 was the only one that was significantly enhanced by insulin treatment. In vitro analysis of thioredoxin 1 revealed a previously undescribed capacity of the enzyme to directly scavenge O(2)(•–). These findings demonstrate that insulin has a role in mitigating cardiac oxidative stress in diabetes via regulation of endogenous antioxidant activity. Elsevier 2021-09-20 /pmc/articles/PMC8473541/ /pubmed/34560411 http://dx.doi.org/10.1016/j.redox.2021.102140 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Short Communication Matsuzaki, Satoshi Eyster, Craig Newhardt, Maria F. Giorgione, Jennifer R. Kinter, Caroline Young, Zachary T. Kinter, Michael Humphries, Kenneth M. Insulin signaling alters antioxidant capacity in the diabetic heart |
title | Insulin signaling alters antioxidant capacity in the diabetic heart |
title_full | Insulin signaling alters antioxidant capacity in the diabetic heart |
title_fullStr | Insulin signaling alters antioxidant capacity in the diabetic heart |
title_full_unstemmed | Insulin signaling alters antioxidant capacity in the diabetic heart |
title_short | Insulin signaling alters antioxidant capacity in the diabetic heart |
title_sort | insulin signaling alters antioxidant capacity in the diabetic heart |
topic | Short Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473541/ https://www.ncbi.nlm.nih.gov/pubmed/34560411 http://dx.doi.org/10.1016/j.redox.2021.102140 |
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