Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae
Glycosphingolipids (GSLs) are products of lipid glycosylation that have been implicated in the development of cardiovascular diseases. In diabetes, the adipocyte microenvironment is characterized by hyperglycemia and inflammation, resulting in high levels of GSLs. Therefore, we sought to assess the...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/20/2453 |
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| author | Imaduddin Mirza Mohamed Haloul Chandra Hassan Mario Masrur Amro Mostafa Francesco M. Bianco Mohamed M. Ali Richard D. Minshall Abeer M. Mahmoud |
| author_facet | Imaduddin Mirza Mohamed Haloul Chandra Hassan Mario Masrur Amro Mostafa Francesco M. Bianco Mohamed M. Ali Richard D. Minshall Abeer M. Mahmoud |
| author_sort | Imaduddin Mirza |
| collection | DOAJ |
| description | Glycosphingolipids (GSLs) are products of lipid glycosylation that have been implicated in the development of cardiovascular diseases. In diabetes, the adipocyte microenvironment is characterized by hyperglycemia and inflammation, resulting in high levels of GSLs. Therefore, we sought to assess the GSL content in extracellular vesicles derived from the adipose tissues (adiposomes) of obese-diabetic (OB-T2D) subjects and their impact on endothelial cell function. To this end, endothelial cells were exposed to adiposomes isolated from OB-T2D versus healthy subjects. Cells were assessed for caveolar integrity and related signaling, such as Src-kinase and caveolin-1 (cav-1) phosphorylation, and functional pathways, such as endothelial nitric oxide synthase (eNOS) activity. Compared with adiposomes from healthy subjects, OB-T2D adiposomes had higher levels of GSLs, especially LacCer and GM3; they promoted cav-1 phosphorylation coupled to an obvious loss of endothelial surface caveolae and induced eNOS-uncoupling, peroxynitrite generation, and cav-1 nitrosylation. These effects were abolished by Src kinase inhibition and were not observed in GSL-depleted adiposomes. At the functional levels, OB-T2D adiposomes reduced nitric oxide production, shear response, and albumin intake in endothelial cells and impaired flow-induced dilation in healthy arterioles. In conclusion, OB-T2D adiposomes carried a detrimental GSL cargo that disturbed endothelial caveolae and the associated signaling. |
| first_indexed | 2024-03-10T21:21:22Z |
| format | Article |
| id | doaj.art-2c5d1cd43e39495a90a0ca28a5ca3562 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T21:21:22Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-2c5d1cd43e39495a90a0ca28a5ca35622023-11-19T16:02:21ZengMDPI AGCells2073-44092023-10-011220245310.3390/cells12202453Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface CaveolaeImaduddin Mirza0Mohamed Haloul1Chandra Hassan2Mario Masrur3Amro Mostafa4Francesco M. Bianco5Mohamed M. Ali6Richard D. Minshall7Abeer M. Mahmoud8Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartments of Anesthesiology and Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USASchool of Business and Non-Profit Management, North Park University, Chicago, IL 60625, USADepartment of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USAGlycosphingolipids (GSLs) are products of lipid glycosylation that have been implicated in the development of cardiovascular diseases. In diabetes, the adipocyte microenvironment is characterized by hyperglycemia and inflammation, resulting in high levels of GSLs. Therefore, we sought to assess the GSL content in extracellular vesicles derived from the adipose tissues (adiposomes) of obese-diabetic (OB-T2D) subjects and their impact on endothelial cell function. To this end, endothelial cells were exposed to adiposomes isolated from OB-T2D versus healthy subjects. Cells were assessed for caveolar integrity and related signaling, such as Src-kinase and caveolin-1 (cav-1) phosphorylation, and functional pathways, such as endothelial nitric oxide synthase (eNOS) activity. Compared with adiposomes from healthy subjects, OB-T2D adiposomes had higher levels of GSLs, especially LacCer and GM3; they promoted cav-1 phosphorylation coupled to an obvious loss of endothelial surface caveolae and induced eNOS-uncoupling, peroxynitrite generation, and cav-1 nitrosylation. These effects were abolished by Src kinase inhibition and were not observed in GSL-depleted adiposomes. At the functional levels, OB-T2D adiposomes reduced nitric oxide production, shear response, and albumin intake in endothelial cells and impaired flow-induced dilation in healthy arterioles. In conclusion, OB-T2D adiposomes carried a detrimental GSL cargo that disturbed endothelial caveolae and the associated signaling.https://www.mdpi.com/2073-4409/12/20/2453extracellular vesiclesadiposomesglycosphingolipids (GSLs)endothelial dysfunctioncaveolaeSrc kinase |
| spellingShingle | Imaduddin Mirza Mohamed Haloul Chandra Hassan Mario Masrur Amro Mostafa Francesco M. Bianco Mohamed M. Ali Richard D. Minshall Abeer M. Mahmoud Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae Cells extracellular vesicles adiposomes glycosphingolipids (GSLs) endothelial dysfunction caveolae Src kinase |
| title | Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae |
| title_full | Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae |
| title_fullStr | Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae |
| title_full_unstemmed | Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae |
| title_short | Adiposomes from Obese-Diabetic Individuals Promote Endothelial Dysfunction and Loss of Surface Caveolae |
| title_sort | adiposomes from obese diabetic individuals promote endothelial dysfunction and loss of surface caveolae |
| topic | extracellular vesicles adiposomes glycosphingolipids (GSLs) endothelial dysfunction caveolae Src kinase |
| url | https://www.mdpi.com/2073-4409/12/20/2453 |
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