MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities
Stress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/8/9/328 |
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| author | Menaka C. Thounaojam Ravirajsinh N. Jadeja Marie Warren Folami L. Powell Raghavan Raju Diana Gutsaeva Sandeep Khurana Pamela M. Martin Manuela Bartoli |
| author_facet | Menaka C. Thounaojam Ravirajsinh N. Jadeja Marie Warren Folami L. Powell Raghavan Raju Diana Gutsaeva Sandeep Khurana Pamela M. Martin Manuela Bartoli |
| author_sort | Menaka C. Thounaojam |
| collection | DOAJ |
| description | Stress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC) were exposed to glucidic stress (high glucose (HG) = 25 mM <span style="font-variant: small-caps;">d</span>-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control <span style="font-variant: small-caps;">l</span>-glucose (LG = 25 mM). HG stimulation of HuREC increased the expression of miR-34a and induced cellular senescence. HG also increased the expression of p16ink4a and p21waf1, while decreasing the histone deacetylase SIRT1. These effects were associated with diminished mitochondrial function and loss of mitochondrial biogenesis factors (i.e., PGC-1α, NRF1, and TFAM). Transfection of the cells with miR-34a inhibitor (IB) halted HG-induced mitochondrial dysfunction and up-regulation of senescence-associated markers, whereas miR-34a mimic promoted cellular senescence and mitochondrial dysfunction. Moreover, HG lowered levels of the mitochondrial antioxidants TrxR2 and SOD2, an effect blunted by miR-34a IB, and promoted by miR-34a mimic. 3’-UTR (3’-untranslated region) reporter assay of both genes validated TrxR2 as a direct target of miR-34a, but not SOD2. Our results show that miR-34a is a key player of HG-induced SAPS in retinal endothelial cells via multiple pathways involved in mitochondrial function and biogenesis. |
| first_indexed | 2024-03-12T07:47:31Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T07:47:31Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-1d522235784e494a93efbbcf08251c812023-09-02T20:49:52ZengMDPI AGAntioxidants2076-39212019-08-018932810.3390/antiox8090328antiox8090328MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant ActivitiesMenaka C. Thounaojam0Ravirajsinh N. Jadeja1Marie Warren2Folami L. Powell3Raghavan Raju4Diana Gutsaeva5Sandeep Khurana6Pamela M. Martin7Manuela Bartoli8Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADivision of Gastroenterology, Hepatology and Nutrition and Weight Management, Geisinger Medical Center, Danville, PA 17822, USADepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAStress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC) were exposed to glucidic stress (high glucose (HG) = 25 mM <span style="font-variant: small-caps;">d</span>-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control <span style="font-variant: small-caps;">l</span>-glucose (LG = 25 mM). HG stimulation of HuREC increased the expression of miR-34a and induced cellular senescence. HG also increased the expression of p16ink4a and p21waf1, while decreasing the histone deacetylase SIRT1. These effects were associated with diminished mitochondrial function and loss of mitochondrial biogenesis factors (i.e., PGC-1α, NRF1, and TFAM). Transfection of the cells with miR-34a inhibitor (IB) halted HG-induced mitochondrial dysfunction and up-regulation of senescence-associated markers, whereas miR-34a mimic promoted cellular senescence and mitochondrial dysfunction. Moreover, HG lowered levels of the mitochondrial antioxidants TrxR2 and SOD2, an effect blunted by miR-34a IB, and promoted by miR-34a mimic. 3’-UTR (3’-untranslated region) reporter assay of both genes validated TrxR2 as a direct target of miR-34a, but not SOD2. Our results show that miR-34a is a key player of HG-induced SAPS in retinal endothelial cells via multiple pathways involved in mitochondrial function and biogenesis.https://www.mdpi.com/2076-3921/8/9/328diabetic retinopathymitochondrial dysfunctionmiR-34avascular senescence |
| spellingShingle | Menaka C. Thounaojam Ravirajsinh N. Jadeja Marie Warren Folami L. Powell Raghavan Raju Diana Gutsaeva Sandeep Khurana Pamela M. Martin Manuela Bartoli MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities Antioxidants diabetic retinopathy mitochondrial dysfunction miR-34a vascular senescence |
| title | MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities |
| title_full | MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities |
| title_fullStr | MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities |
| title_full_unstemmed | MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities |
| title_short | MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities |
| title_sort | microrna 34a mir 34a mediates retinal endothelial cell premature senescence through mitochondrial dysfunction and loss of antioxidant activities |
| topic | diabetic retinopathy mitochondrial dysfunction miR-34a vascular senescence |
| url | https://www.mdpi.com/2076-3921/8/9/328 |
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