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Sirt1/Drp1 Pathway Reduces Microvascular Endothelial Cell Injury in Diabetic Pateints' Hearts by Inhibiting Excessive
Shimeng Huang1, Yuanbo Gao1, Ying Wang2
1Department of Cardiology, Affiliated People's Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu, China.
Insights
Sirtuin 1 (Sirt1) protects cardiac microvascular endothelial cells from diabetic injury by inhibiting excessive mitochondrial division via the Sirt1/Drp1 pathway, improving heart function in diabetes.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Biology
- Diabetic Complications
Background:
- Diabetic patients exhibit reduced cardiac microvessels, increasing cardiac complications and mortality.
- Sirtuin 1 (Sirt1) is investigated for its role in diabetic cardiac microvascular endothelial cell (CMEC) injury.
Purpose of the Study:
- To investigate the role of Sirtuin 1 (Sirt1) in diabetic cardiac microvascular endothelial cell (CMEC) injury.
- To elucidate the underlying mechanism involving the Sirt1/Drp1 pathway.
Main Methods:
- Established type 2 diabetes mouse and CMEC models.
- Assessed microvessel density (CD31), mitochondrial ROS, and morphology.
- Evaluated CMEC angiogenesis, viability (CCK-8), injury (LDH), and apoptosis (TUNEL, Caspase-3).
Main Results:
- Decreased Sirt1 expression correlated with reduced cardiac microvessel density in diabetic mice.
- High glucose/palmitic acid treatment decreased Sirt1 and p-Drp1, increased cleaved Caspase-3, ROS, and mitochondrial division, impairing CMEC function.
- Enhanced Sirt1 expression/function reduced mitochondrial division, apoptosis, and improved CMEC function.
Conclusions:
- The Sirt1/Drp1 pathway mitigates CMEC injury in diabetes by inhibiting excessive mitochondrial division.
- Targeting the Sirt1/Drp1 pathway may offer therapeutic potential for diabetic cardiac complications.
Background:
Cardiac microvessels are significantly reduced in diabetic patients, which is accompanied by a significant increase in the incidence of diabetic cardiac complications and increased mortality. This study aimed to investigate the role and possible mechanism of sirtuin 1 (Sirt1) in microvascular endothelial cell injury in diabetic hearts.
Methods:
Type 2 diabetes mouse models and cardiac microvascular endothelial cell (CMEC) cell models were established. Cardiac microvessel density (MVD) was detected using Platelet- Endothelial Cell Adhesion Molecule 1 (CD31) immunohistochemistry. Mitochondrial reactive oxygen species (ROS) was detected with MitoSOX and morphology was observed with mitochondrial staining. CMECs angiogenesis was evaluated via scratch and angiogenesis assays. We measured cell viability with a Cell Counting Kit (CCK)-8 assay and cell injury with lactate dehydrogenase (LDH) release assay. We assessed apoptosis using TUNEL staining, Caspase-3 activity, and Western blot.
Results:
The decrease in Sirt1 protein expression was accompanied by a decrease in cardiac microvessel density in type 2 diabetic mice. After 48 h of treating the CMECs with high-glucose and palmitic acid, it was discovered that the expression of Sirt1 and dynamin-related protein 1 (Drp1) Ser637 phosphorylated protein decreased, while the expression of Cleaved Caspase-3 protein increased. Also, the angiogenesis ability of endothelial cells was decreased, while mitochondrial ROS and mitochondrial division were increased, which culminated in aggravated endothelial cell injury and increased endothelial cell apoptosis. Increased Sirt1 protein expression and function at the gene and drug levels alleviated excessive mitochondrial division, reduced apoptosis, and improved the function of CMECs by increasing the phosphorylation of Drp1 Ser637.
Conclusion:
Under diabetic conditions, the Sirt1/Drp1 pathway reduces injury to CMECs by inhibiting excessive mitochondrial division.
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