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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2023

Open Access 01-12-2023 | Diabetic Cardiomyopathy | Research

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

Authors: Keshav Gopal, Qutuba G. Karwi, Seyed Amirhossein Tabatabaei Dakhili, Cory S. Wagg, Liyan Zhang, Qiuyu Sun, Christina T. Saed, Sai Panidarapu, Riccardo Perfetti, Ravichandran Ramasamy, John R. Ussher, Gary D. Lopaschuk

Published in: Cardiovascular Diabetology | Issue 1/2023

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Abstract

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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Metadata
Title
Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation
Authors
Keshav Gopal
Qutuba G. Karwi
Seyed Amirhossein Tabatabaei Dakhili
Cory S. Wagg
Liyan Zhang
Qiuyu Sun
Christina T. Saed
Sai Panidarapu
Riccardo Perfetti
Ravichandran Ramasamy
John R. Ussher
Gary D. Lopaschuk
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-023-01811-w

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