Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress
Abstract Background Diabetes mellitus (DM), characterized by hyperglycemia, is intricately linked with cardiovascular complications. Hyperglycemia induces oxidative stress, compromising mitochondria energy metabolism disturbances, leading to cardiomyocyte hypoxia and dysregulation of hypoxia-inducib...
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| Language: | English |
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BMC
2025-02-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | https://doi.org/10.1186/s12933-025-02601-2 |
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| author | Tingting Fang Congcong Ma Bingyun Yang Meiyu Zhao Luning Sun Ningning Zheng |
| author_facet | Tingting Fang Congcong Ma Bingyun Yang Meiyu Zhao Luning Sun Ningning Zheng |
| author_sort | Tingting Fang |
| collection | DOAJ |
| description | Abstract Background Diabetes mellitus (DM), characterized by hyperglycemia, is intricately linked with cardiovascular complications. Hyperglycemia induces oxidative stress, compromising mitochondria energy metabolism disturbances, leading to cardiomyocyte hypoxia and dysregulation of hypoxia-inducible factor-1α (HIF-1α), thereby exacerbating diabetic myocardial injury. Roxadustat (FG-4592), as an inhibitor of HIF-PHD, reduces HIF-1α degradation and regulates the transcription and function of downstream target genes. This study explores the protective effect of FG-4592 on the diabetic myocardium and further investigates the specific mechanisms responsible for this action. Methods We established diabetic myocardial injury mice and high glucose-induced rat cardiomyocyte models, administered FG-4592 pretreatment to clarify the protective effects and related mechanisms of FG-4592 on diabetic myocardial injury by detecting changes in oxidative stress, mitochondrial function, and related pathways. Results FG-4592 demonstrated cardioprotective effects in diabetic mice by regulating mitochondrial structure and function, as well as maintaining oxidative stress balance in the myocardium. It stabilized HIF-1α, activated UCP2, and enhanced the PI3K/AKT/Nrf2 pathway, reducing mitochondrial superoxide production, improving mitochondrial respiratory potential, and modulating oxidative stress markers in high glucose-induced cardiomyocytes. Conclusions FG-4592 exerts protective effects against diabetic myocardial injury by reducing oxidative stress. The mechanism is linked with the upregulation of HIF-1α and UCP2, which subsequently activate the PI3K/AKT/Nrf2 signaling pathway. |
| format | Article |
| id | doaj-art-1afe5c6077794f2383e0226157846a17 |
| institution | Kabale University |
| issn | 1475-2840 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj-art-1afe5c6077794f2383e0226157846a172025-02-09T12:10:59ZengBMCCardiovascular Diabetology1475-28402025-02-0124111810.1186/s12933-025-02601-2Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stressTingting Fang0Congcong Ma1Bingyun Yang2Meiyu Zhao3Luning Sun4Ningning Zheng5Department of Pathophysiology, College of Basic Medical Science, China Medical UniversityDepartment of Pathophysiology, College of Basic Medical Science, China Medical UniversityDepartment of Pathophysiology, College of Basic Medical Science, China Medical UniversityDepartment of Pathophysiology, College of Basic Medical Science, China Medical UniversityDepartment of Pathophysiology, College of Basic Medical Science, China Medical UniversityDepartment of Pathophysiology, College of Basic Medical Science, China Medical UniversityAbstract Background Diabetes mellitus (DM), characterized by hyperglycemia, is intricately linked with cardiovascular complications. Hyperglycemia induces oxidative stress, compromising mitochondria energy metabolism disturbances, leading to cardiomyocyte hypoxia and dysregulation of hypoxia-inducible factor-1α (HIF-1α), thereby exacerbating diabetic myocardial injury. Roxadustat (FG-4592), as an inhibitor of HIF-PHD, reduces HIF-1α degradation and regulates the transcription and function of downstream target genes. This study explores the protective effect of FG-4592 on the diabetic myocardium and further investigates the specific mechanisms responsible for this action. Methods We established diabetic myocardial injury mice and high glucose-induced rat cardiomyocyte models, administered FG-4592 pretreatment to clarify the protective effects and related mechanisms of FG-4592 on diabetic myocardial injury by detecting changes in oxidative stress, mitochondrial function, and related pathways. Results FG-4592 demonstrated cardioprotective effects in diabetic mice by regulating mitochondrial structure and function, as well as maintaining oxidative stress balance in the myocardium. It stabilized HIF-1α, activated UCP2, and enhanced the PI3K/AKT/Nrf2 pathway, reducing mitochondrial superoxide production, improving mitochondrial respiratory potential, and modulating oxidative stress markers in high glucose-induced cardiomyocytes. Conclusions FG-4592 exerts protective effects against diabetic myocardial injury by reducing oxidative stress. The mechanism is linked with the upregulation of HIF-1α and UCP2, which subsequently activate the PI3K/AKT/Nrf2 signaling pathway.https://doi.org/10.1186/s12933-025-02601-2RoxadustatDiabetes mellitusDiabetic myocardial injuryUncoupling protein 2Hypoxia-inducible factor -1αOxidative stress |
| spellingShingle | Tingting Fang Congcong Ma Bingyun Yang Meiyu Zhao Luning Sun Ningning Zheng Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress Cardiovascular Diabetology Roxadustat Diabetes mellitus Diabetic myocardial injury Uncoupling protein 2 Hypoxia-inducible factor -1α Oxidative stress |
| title | Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress |
| title_full | Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress |
| title_fullStr | Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress |
| title_full_unstemmed | Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress |
| title_short | Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress |
| title_sort | roxadustat improves diabetic myocardial injury by upregulating hif 1α ucp2 against oxidative stress |
| topic | Roxadustat Diabetes mellitus Diabetic myocardial injury Uncoupling protein 2 Hypoxia-inducible factor -1α Oxidative stress |
| url | https://doi.org/10.1186/s12933-025-02601-2 |
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