Related Experiment Video
Updated: May 10, 2025
Isolation and Identification of Vascular Endothelial Cells from Distinct Adipose Depots for Downstream Applications
Published on: June 10, 2022
SETD7 drives diabetic endothelial dysfunction through FBXO45-mediated GPX4 ubiquitylation
Wen Zhong1, Ruoxue Chen1, Jialin Zhao1
1Phenome Research Center of TCM, Department of Traditional Chinese Medicine, Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, 825, Zhangheng Road, Pudong New District, Shanghai, 201203, China.
Background:
Vasculopathy is the most prevalent complication of diabetes. Endothelial damage, a primary contributor to hyperglycemic vascular complications, impacts macro- and micro-vasculatures, causing functional impairment of multiple organs. SETD7 was initially identified as a transcriptional activator based on its ability to methylate histone 3 lysine 4. However, its function in the context of diabetic endothelial dysfunction remains poorly understood. This study aims to elucidate the involvement and underlying mechanisms of SETD7 in diabetic endothelial dysfunction.
Methods:
SETD7 knockout mice were generated to investigate the effects of SETD7 on Streptozotocin (STZ)-induced hyperglycemia and vascular endothelial injury. Endothelial-specific SETD7 interruption adeno-associated virus (AAV) system was utilized to investigate the effects of SETD7 on diabetic vascular endothelial injury in BKS-DB(Lepr) KO/KO (db/db) mice. In vitro manipulation of SETD7 activation or knockdown was conducted to assess its regulation on the lipid peroxidation, oxidative stress, and cell function of primary rat aortic endothelial cells (RAECs) under high glucose conditions.
Results:
Our study revealed that knockout and endothelial deficiency of SETD7 partially restored damaged vascular function and attenuated the inflammatory response caused by high glucose in both STZ-induced and db/db mice. Moreover, SETD7 activation aggravated oxidative stress injury and resulted in profound dysfunction through Glutathione Peroxidase 4 (GPX4)-mediated lipid peroxidation in RAECs. Mechanistically, SETD7 deficiency reduced p53 mono-methylation and blocked FBXO45 transcription, thereby inhibiting the protein degradation of GPX4 and subsequent lipid peroxidation as well as oxidative stress.
Conclusions:
In summary, our study demonstrates that SETD7-p53-FBXO45-GPX4 is involved in high glucose-induced oxidative stress injury and exacerbated endothelial dysfunction, which offering great significance for mitigating hyperglycemia-induced endothelial damage.
Insights
Diabetic endothelial dysfunction is worsened by SETD7, which promotes oxidative stress and lipid peroxidation. Inhibiting SETD7 partially restores vascular function and reduces hyperglycemia-induced damage.
Area of Science:
- Endocrinology
- Molecular Biology
- Cardiovascular Research
Background:
- Diabetic vasculopathy is a major complication, with endothelial damage contributing to organ dysfunction.
- The role of SETD7 (histone methyltransferase) in diabetic endothelial dysfunction is not well understood.
- This study investigates SETD7's mechanisms in high glucose-induced endothelial injury.
Purpose of the Study:
- To elucidate the involvement and underlying mechanisms of SETD7 in diabetic endothelial dysfunction.
- To investigate the effects of SETD7 on hyperglycemia-induced vascular injury.
- To assess SETD7's regulation of oxidative stress and lipid peroxidation in endothelial cells.
Main Methods:
- Utilized SETD7 knockout mice and endothelial-specific SETD7 interruption via AAV in db/db mice.
- Assessed effects on Streptozotocin (STZ)-induced hyperglycemia and vascular injury.
- Performed in vitro studies on primary rat aortic endothelial cells (RAECs) under high glucose conditions, manipulating SETD7.
Main Results:
- SETD7 deficiency partially restored vascular function and reduced inflammation in diabetic mouse models.
- SETD7 activation exacerbated oxidative stress and endothelial dysfunction via Glutathione Peroxidase 4 (GPX4)-mediated lipid peroxidation.
- SETD7 deficiency reduced p53 mono-methylation, blocked FBXO45 transcription, inhibiting GPX4 degradation.
Conclusions:
- The SETD7-p53-FBXO45-GPX4 pathway is implicated in high glucose-induced oxidative stress and endothelial dysfunction.
- Targeting this pathway may mitigate hyperglycemia-induced endothelial damage.
- Findings highlight SETD7 as a potential therapeutic target for diabetic vascular complications.
More Related Videos
05:58Mouse Electroacupuncture Fixation Device Fabrication for Electroacupuncture Pretreatment in Diabetic Cardiomyopathy Mouse Model
Published on: April 18, 2025
06:35Author Spotlight: Insights into Cardiometabolic Diseases with Subcutaneous Adipose Tissue Microvasculature Studies
Published on: April 5, 2024
