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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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Autores principales: Thounaojam, Menaka C., Jadeja, Ravirajsinh N., Warren, Marie, Powell, Folami L., Raju, Raghavan, Gutsaeva, Diana, Khurana, Sandeep, Martin, Pamela M., Bartoli, Manuela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769710/
https://www.ncbi.nlm.nih.gov/pubmed/31443378
http://dx.doi.org/10.3390/antiox8090328
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author Thounaojam, Menaka C.
Jadeja, Ravirajsinh N.
Warren, Marie
Powell, Folami L.
Raju, Raghavan
Gutsaeva, Diana
Khurana, Sandeep
Martin, Pamela M.
Bartoli, Manuela
author_facet Thounaojam, Menaka C.
Jadeja, Ravirajsinh N.
Warren, Marie
Powell, Folami L.
Raju, Raghavan
Gutsaeva, Diana
Khurana, Sandeep
Martin, Pamela M.
Bartoli, Manuela
author_sort Thounaojam, Menaka C.
collection PubMed
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 d-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control l-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.
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spelling pubmed-67697102019-10-30 MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities Thounaojam, Menaka C. Jadeja, Ravirajsinh N. Warren, Marie Powell, Folami L. Raju, Raghavan Gutsaeva, Diana Khurana, Sandeep Martin, Pamela M. Bartoli, Manuela Antioxidants (Basel) Article 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 d-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control l-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. MDPI 2019-08-22 /pmc/articles/PMC6769710/ /pubmed/31443378 http://dx.doi.org/10.3390/antiox8090328 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thounaojam, Menaka C.
Jadeja, Ravirajsinh N.
Warren, Marie
Powell, Folami L.
Raju, Raghavan
Gutsaeva, Diana
Khurana, Sandeep
Martin, Pamela M.
Bartoli, Manuela
MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769710/
https://www.ncbi.nlm.nih.gov/pubmed/31443378
http://dx.doi.org/10.3390/antiox8090328
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