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

doi:10.3390/antiox8090328

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MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities

Menaka C. Thounaojam

¹,

Ravirajsinh N. Jadeja

²,

³,

²,

³,

¹,

⁴,

² and

^1,*

Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA

Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA

⁴

Division of Gastroenterology, Hepatology and Nutrition and Weight Management, Geisinger Medical Center, Danville, PA 17822, USA

Author to whom correspondence should be addressed.

Antioxidants 2019, 8(9), 328; https://doi.org/10.3390/antiox8090328

Received: 17 July 2019 / Revised: 16 August 2019 / Accepted: 20 August 2019 / Published: 22 August 2019

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Abstract

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. View Full-Text

Keywords: diabetic retinopathy; mitochondrial dysfunction; miR-34a; vascular senescence

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MDPI and ACS Style

Thounaojam, M.C.; Jadeja, R.N.; Warren, M.; Powell, F.L.; Raju, R.; Gutsaeva, D.; Khurana, S.; Martin, P.M.; Bartoli, M. MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities. Antioxidants 2019, 8, 328. https://doi.org/10.3390/antiox8090328

AMA Style

Thounaojam MC, Jadeja RN, Warren M, Powell FL, Raju R, Gutsaeva D, Khurana S, Martin PM, Bartoli M. MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities. Antioxidants. 2019; 8(9):328. https://doi.org/10.3390/antiox8090328

Chicago/Turabian Style

Thounaojam, Menaka C., Ravirajsinh N. Jadeja, Marie Warren, Folami L. Powell, Raghavan Raju, Diana Gutsaeva, Sandeep Khurana, Pamela M. Martin, and Manuela Bartoli. 2019. "MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities" Antioxidants 8, no. 9: 328. https://doi.org/10.3390/antiox8090328

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MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities

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