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Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation

BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodel...

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Autores principales: Gopal, Keshav, Karwi, Qutuba G., Tabatabaei Dakhili, Seyed Amirhossein, Wagg, Cory S., Zhang, Liyan, Sun, Qiuyu, Saed, Christina T., Panidarapu, Sai, Perfetti, Riccardo, Ramasamy, Ravichandran, Ussher, John R., Lopaschuk, Gary D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053619/
https://www.ncbi.nlm.nih.gov/pubmed/36978133
http://dx.doi.org/10.1186/s12933-023-01811-w
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author Gopal, Keshav
Karwi, Qutuba G.
Tabatabaei Dakhili, Seyed Amirhossein
Wagg, Cory S.
Zhang, Liyan
Sun, Qiuyu
Saed, Christina T.
Panidarapu, Sai
Perfetti, Riccardo
Ramasamy, Ravichandran
Ussher, John R.
Lopaschuk, Gary D.
author_facet Gopal, Keshav
Karwi, Qutuba G.
Tabatabaei Dakhili, Seyed Amirhossein
Wagg, Cory S.
Zhang, Liyan
Sun, Qiuyu
Saed, Christina T.
Panidarapu, Sai
Perfetti, Riccardo
Ramasamy, Ravichandran
Ussher, John R.
Lopaschuk, Gary D.
author_sort Gopal, Keshav
collection PubMed
description BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism. METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism. RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min(−1) g dry wt(−1) in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy. CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.
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spelling pubmed-100536192023-03-30 Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation Gopal, Keshav Karwi, Qutuba G. Tabatabaei Dakhili, Seyed Amirhossein Wagg, Cory S. Zhang, Liyan Sun, Qiuyu Saed, Christina T. Panidarapu, Sai Perfetti, Riccardo Ramasamy, Ravichandran Ussher, John R. Lopaschuk, Gary D. Cardiovasc Diabetol Research BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism. METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism. RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min(−1) g dry wt(−1) in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy. CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes. BioMed Central 2023-03-28 /pmc/articles/PMC10053619/ /pubmed/36978133 http://dx.doi.org/10.1186/s12933-023-01811-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Gopal, Keshav
Karwi, Qutuba G.
Tabatabaei Dakhili, Seyed Amirhossein
Wagg, Cory S.
Zhang, Liyan
Sun, Qiuyu
Saed, Christina T.
Panidarapu, Sai
Perfetti, Riccardo
Ramasamy, Ravichandran
Ussher, John R.
Lopaschuk, Gary D.
Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
title Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
title_full Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
title_fullStr Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
title_full_unstemmed Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
title_short Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
title_sort aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053619/
https://www.ncbi.nlm.nih.gov/pubmed/36978133
http://dx.doi.org/10.1186/s12933-023-01811-w
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