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Folic acid alleviates endothelial dysfunction caused by T2DM-induced ferroptosis by activating the SIRT6/NRF2/GPX4
Lei Hong1,2,3, Xinqi Lou1,2,3, Yingjie Zha1,2,3
1Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China. szkjcyy_ajz@126.com.
Abstract:
Cardiovascular complications associated with type 2 diabetes mellitus (T2DM) pose a serious threat to human health. Folic acid deficiency is associated with various diseases, including atherosclerosis. However, it remains unclear whether folic acid has a protective effect on vascular injury induced by T2DM. To address this, folic acid was administered to db/db or db/dm mice, and endothelial cells were treated under high-fat and high-glucose (HGF) conditions to evaluate the effect of folic acid on cell viability. RNA sequencing was performed to explore the potential targets of folic acid. The results indicated that folic acid alleviates endothelial cell injury and ferroptosis in T2DM by upregulating the SIRT6/NRF2 pathway and mitigating oxidative stress, Fe2+ accumulation and lipid peroxidation. The SIRT6 inhibitor counteracted the protective effect of folic acid on endothelial cells in vitro. Overall, folic acid may be a promising drug for treating or alleviating endothelial dysfunction in T2DM.
Insights
Folic acid protects against type 2 diabetes-induced vascular injury by reducing cell damage and oxidative stress. It works by boosting the SIRT6/NRF2 pathway, offering potential therapeutic benefits for endothelial dysfunction.
Area of Science:
- Biomedical Science
- Cardiovascular Research
- Metabolic Disorders
Background:
- Cardiovascular complications are a major health risk in type 2 diabetes mellitus (T2DM).
- Folic acid deficiency is linked to atherosclerosis, but its role in T2DM-related vascular injury is unknown.
- Understanding folic acid's protective mechanisms in T2DM vascular injury is crucial.
Purpose of the Study:
- To investigate the protective effects of folic acid on T2DM-induced endothelial cell injury.
- To explore the molecular targets and pathways involved in folic acid's action.
Main Methods:
- Administered folic acid to T2DM mouse models (db/db or db/dm).
- Treated endothelial cells with high-fat and high-glucose (HGF) conditions.
- Utilized RNA sequencing to identify potential molecular targets.
- Assessed cell viability, oxidative stress, iron accumulation, and lipid peroxidation.
Main Results:
- Folic acid alleviated endothelial cell injury and ferroptosis in T2DM.
- This protection was mediated by the upregulation of the SIRT6/NRF2 pathway.
- Folic acid mitigated oxidative stress, Fe2+ accumulation, and lipid peroxidation.
- A SIRT6 inhibitor reversed the protective effects of folic acid in vitro.
Conclusions:
- Folic acid demonstrates a protective effect against T2DM-induced endothelial dysfunction.
- The SIRT6/NRF2 pathway is a key mediator of folic acid's benefits.
- Folic acid shows promise as a therapeutic agent for T2DM-related vascular complications.
