{"title":"Sirt1/Drp1 Pathway Reduces Microvascular Endothelial Cell Injury in Diabetic Pateints' Hearts by Inhibiting Excessive Mitochondrial Division.","authors":"Shimeng Huang, Yuanbo Gao, Ying Wang, Siyu Zhao, Bing Lu, Aibin Tao","doi":"10.2174/0115701611370387250122050842","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Under diabetic conditions, the Sirt1/Drp1 pathway reduces injury to CMECs by inhibiting excessive mitochondrial division.</p>","PeriodicalId":11278,"journal":{"name":"Current vascular pharmacology","volume":" ","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current vascular pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0115701611370387250122050842","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
Current Vascular Pharmacology publishes clinical and research-based reviews/mini-reviews, original research articles, letters, debates, drug clinical trial studies and guest edited issues to update all those concerned with the treatment of vascular disease, bridging the gap between clinical practice and ongoing research.
Vascular disease is the commonest cause of death in Westernized countries and its incidence is on the increase in developing countries. It follows that considerable research is directed at establishing effective treatment for acute vascular events. Long-term treatment has also received considerable attention (e.g. for symptomatic relief). Furthermore, effective prevention, whether primary or secondary, is backed by the findings of several landmark trials. Vascular disease is a complex field with primary care physicians and nurse practitioners as well as several specialties involved. The latter include cardiology, vascular and cardio thoracic surgery, general medicine, radiology, clinical pharmacology and neurology (stroke units).
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