Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells
Abstract Background Atherosclerosis is a common co-morbidity of type 2 diabetes mellitus. Monocyte recruitment by an activated endothelium and the pro-inflammatory activity of the resulting macrophages are critical components of atherosclerosis. Exosomal transfer of microRNAs has emerged as a paracr...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-023-01833-4 |
| _version_ | 1797827732472594432 |
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| author | Heng Yu Hunter F. Douglas Donald Wathieu Ryan A. Braun Christine Edomwande Daniel J. Lightell Jr. Thaidan Pham Natasha C. Klingenberg Shelia Pugh Bishop Damir B. Khismatullin T. Cooper Woods |
| author_facet | Heng Yu Hunter F. Douglas Donald Wathieu Ryan A. Braun Christine Edomwande Daniel J. Lightell Jr. Thaidan Pham Natasha C. Klingenberg Shelia Pugh Bishop Damir B. Khismatullin T. Cooper Woods |
| author_sort | Heng Yu |
| collection | DOAJ |
| description | Abstract Background Atherosclerosis is a common co-morbidity of type 2 diabetes mellitus. Monocyte recruitment by an activated endothelium and the pro-inflammatory activity of the resulting macrophages are critical components of atherosclerosis. Exosomal transfer of microRNAs has emerged as a paracrine signaling mechanism regulating atherosclerotic plaque development. MicroRNAs-221 and -222 (miR-221/222) are elevated in vascular smooth muscle cells (VSMCs) of diabetic patients. We hypothesized that the transfer of miR-221/222 via VSMC-derived exosomes from diabetic sources (DVEs) promotes increased vascular inflammation and atherosclerotic plaque development. Methods Exosomes were obtained from VSMCs, following exposure to non-targeting or miR-221/-222 siRNA (-KD), isolated from diabetic (DVEs) and non-diabetic (NVEs) sources and their miR-221/-222 content was measured using droplet digital PCR (ddPCR). Expression of adhesion molecules and the adhesion of monocytes was measured following exposure to DVEs and NVEs. Macrophage phenotype following exposure to DVEs was determined by measuring mRNA markers and secreted cytokines. Age-matched apolipoprotein-E-deficient mice null (ApoE−/−) mice were maintained on Western diet for 6 weeks and received injections of saline, NVEs, NVE-KDs, DVEs or DVE-KDs every other day. Atherosclerotic plaque formation was measured using Oil Red Oil staining. Results Exposure of human umbilical vein and coronary artery endothelial cells to DVEs, but not NVEs, NVE-KDs, or DVE-KDs promoted increased intercellular adhesion molecule-1 expression and monocyte adhesion. DVEs but not NVEs, NVE-KDs, or DVE-KDs also promoted pro-inflammatory polarization of human monocytes in a miR-221/222 dependent manner. Finally, intravenous administration of DVEs, but not NVEs, resulted in a significant increase in atherosclerotic plaque development. Conclusion These data identify a novel paracrine signaling pathway that promotes the cardiovascular complications of diabetes mellitus. |
| first_indexed | 2024-04-09T12:53:05Z |
| format | Article |
| id | doaj.art-c0c99071de8843f9b17cdbb4ce6cd910 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-04-09T12:53:05Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-c0c99071de8843f9b17cdbb4ce6cd9102023-05-14T11:07:32ZengBMCCardiovascular Diabetology1475-28402023-05-0122111510.1186/s12933-023-01833-4Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cellsHeng Yu0Hunter F. Douglas1Donald Wathieu2Ryan A. Braun3Christine Edomwande4Daniel J. Lightell Jr.5Thaidan Pham6Natasha C. Klingenberg7Shelia Pugh Bishop8Damir B. Khismatullin9T. Cooper Woods10Department of Biomedical Engineering, Tulane UniversityDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Physiology, Tulane University School of MedicineDepartment of Biomedical Engineering, Tulane UniversityDepartment of Physiology, Tulane University School of MedicineAbstract Background Atherosclerosis is a common co-morbidity of type 2 diabetes mellitus. Monocyte recruitment by an activated endothelium and the pro-inflammatory activity of the resulting macrophages are critical components of atherosclerosis. Exosomal transfer of microRNAs has emerged as a paracrine signaling mechanism regulating atherosclerotic plaque development. MicroRNAs-221 and -222 (miR-221/222) are elevated in vascular smooth muscle cells (VSMCs) of diabetic patients. We hypothesized that the transfer of miR-221/222 via VSMC-derived exosomes from diabetic sources (DVEs) promotes increased vascular inflammation and atherosclerotic plaque development. Methods Exosomes were obtained from VSMCs, following exposure to non-targeting or miR-221/-222 siRNA (-KD), isolated from diabetic (DVEs) and non-diabetic (NVEs) sources and their miR-221/-222 content was measured using droplet digital PCR (ddPCR). Expression of adhesion molecules and the adhesion of monocytes was measured following exposure to DVEs and NVEs. Macrophage phenotype following exposure to DVEs was determined by measuring mRNA markers and secreted cytokines. Age-matched apolipoprotein-E-deficient mice null (ApoE−/−) mice were maintained on Western diet for 6 weeks and received injections of saline, NVEs, NVE-KDs, DVEs or DVE-KDs every other day. Atherosclerotic plaque formation was measured using Oil Red Oil staining. Results Exposure of human umbilical vein and coronary artery endothelial cells to DVEs, but not NVEs, NVE-KDs, or DVE-KDs promoted increased intercellular adhesion molecule-1 expression and monocyte adhesion. DVEs but not NVEs, NVE-KDs, or DVE-KDs also promoted pro-inflammatory polarization of human monocytes in a miR-221/222 dependent manner. Finally, intravenous administration of DVEs, but not NVEs, resulted in a significant increase in atherosclerotic plaque development. Conclusion These data identify a novel paracrine signaling pathway that promotes the cardiovascular complications of diabetes mellitus.https://doi.org/10.1186/s12933-023-01833-4ExosomesmicroRNAAtherogenesis/atherosclerosisEndothelial dysfunctionMacrophage activationVascular inflammation |
| spellingShingle | Heng Yu Hunter F. Douglas Donald Wathieu Ryan A. Braun Christine Edomwande Daniel J. Lightell Jr. Thaidan Pham Natasha C. Klingenberg Shelia Pugh Bishop Damir B. Khismatullin T. Cooper Woods Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells Cardiovascular Diabetology Exosomes microRNA Atherogenesis/atherosclerosis Endothelial dysfunction Macrophage activation Vascular inflammation |
| title | Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells |
| title_full | Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells |
| title_fullStr | Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells |
| title_full_unstemmed | Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells |
| title_short | Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells |
| title_sort | diabetes is accompanied by secretion of pro atherosclerotic exosomes from vascular smooth muscle cells |
| topic | Exosomes microRNA Atherogenesis/atherosclerosis Endothelial dysfunction Macrophage activation Vascular inflammation |
| url | https://doi.org/10.1186/s12933-023-01833-4 |
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