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Updated: Feb 7, 2026
Modeling and Evaluation of Murine Diabetic Cardiomyopathy Model
Published on: November 29, 2024
Exogenous hydrogen sulfide attenuates the development of diabetic cardiomyopathy via the FoxO1 pathway
Peng Ye1, Yue Gu1, Yan-Rong Zhu1
1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Insights
Hydrogen sulfide (H2S) improves cardiac function in diabetic cardiomyopathy by regulating the nuclear factor FoxO1. This study reveals H2S as a potential therapeutic regulator for diabetic heart disease.
Area of Science:
- Cardiovascular Biology
- Metabolic Diseases
- Molecular Medicine
Background:
- Diabetic cardiomyopathy (DCM) is a complex condition linked to oxidative stress, inflammation, and apoptosis.
- Exogenous hydrogen sulfide (H2S) shows promise in mitigating DCM, but its precise mechanism remains unclear.
- The transcription factor Forkhead box protein O (FoxO1) is implicated in cardiovascular disease and its role in DCM is gaining attention.
Purpose of the Study:
- To investigate the interaction between hydrogen sulfide (H2S) and nuclear FoxO1 in the context of diabetic cardiomyopathy (DCM).
- To elucidate the molecular mechanisms by which H2S influences cardiac function and cellular processes in DCM.
Main Methods:
- Diabetic cardiomyopathy was induced in mice using streptozotocin and treated with an H2S donor.
- In vitro studies utilized H9C2 cardiomyoblasts and neonatal rat cardiomyocytes exposed to high glucose and H2S donors, with or without an Akt inhibitor.
- FoxO1 phosphorylation, subcellular localization, cardiac structure, and function were assessed using biochemical, cellular, and histological analyses.
Main Results:
- Exogenous H2S administration improved cardiac function, reduced cardiac hypertrophy and fibrosis in diabetic mice.
- H2S treatment ameliorated high-glucose-induced oxidative stress and apoptosis in cardiac cells.
- H2S promoted FoxO1 phosphorylation and nuclear exclusion, a process independent of Akt inhibition; mutations preventing this phosphorylation blocked H2S's protective effects.
Conclusions:
- Hydrogen sulfide (H2S) acts as a novel regulator of FoxO1 in cardiac cells, influencing its nuclear localization and function.
- These findings provide mechanistic insights into H2S's protective effects against diabetic cardiomyopathy.
- Hydrogen sulfide demonstrates significant potential as a therapeutic agent for inhibiting the progression of diabetic cardiomyopathy.
Background:
Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy (DCM) by inhibiting oxidative stress, inflammation, and apoptosis. However, the underlying mechanism is not fully understood. Nuclear expression and function of the transcription factor Forkhead box protein O (FoxO1) have been associated with cardiovascular diseases, and thus, the importance of FoxO1 in DCM has gained increasing attention. This study was designed to investigate the interactions between hydrogen sulfide (H2 S) and nuclear FoxO1 in DCM.
Methods:
Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H2 S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow-releasing H2 S donor GYY4137 before high-glucose (HG) exposure with or without pretreatment with the Akt inhibitor MK-2206 2HCl. Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells, NRCMs, and cardiac tissues from normal and diabetic mice. Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals.
Results:
The echocardiographic and histopathological data indicated that exogenous H2 S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H2 S also improved HG-induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H2 S induced FoxO1 phosphorylation and nuclear exclusion in vitro and in vivo, and this function was not inhibited by MK-2206 2HCl. Alanine substitution mutation of three sites in FoxO1-enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H2 S could not prevent HG-induced nuclear retention.
Conclusions:
Our data indicate that H2 S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H2 S in inhibiting the progression of DCM.
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