Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1

We have recently found that diabetes-induced premature senescence of retinal endothelial cells is accompanied by NOX2-NADPH oxidase-induced increases in the ureohydrolase enzyme arginase 1 (A1). Here, we used genetic strategies to determine the specific involvement of A1 in diabetes-induced endothel...

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Autores principales: Shosha, Esraa, Xu, Zhimin, Narayanan, S. Priya, Lemtalsi, Tahira, Fouda, Abdelrahman Y., Rojas, Modesto, Xing, Ji, Fulton, David, Caldwell, R. William, Caldwell, Ruth B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979610/
https://www.ncbi.nlm.nih.gov/pubmed/29673160
http://dx.doi.org/10.3390/ijms19041215
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author Shosha, Esraa
Xu, Zhimin
Narayanan, S. Priya
Lemtalsi, Tahira
Fouda, Abdelrahman Y.
Rojas, Modesto
Xing, Ji
Fulton, David
Caldwell, R. William
Caldwell, Ruth B.
author_facet Shosha, Esraa
Xu, Zhimin
Narayanan, S. Priya
Lemtalsi, Tahira
Fouda, Abdelrahman Y.
Rojas, Modesto
Xing, Ji
Fulton, David
Caldwell, R. William
Caldwell, Ruth B.
author_sort Shosha, Esraa
collection PubMed
description We have recently found that diabetes-induced premature senescence of retinal endothelial cells is accompanied by NOX2-NADPH oxidase-induced increases in the ureohydrolase enzyme arginase 1 (A1). Here, we used genetic strategies to determine the specific involvement of A1 in diabetes-induced endothelial cell senescence. We used A1 knockout mice and wild type mice that were rendered diabetic with streptozotocin and retinal endothelial cells (ECs) exposed to high glucose or transduced with adenovirus to overexpress A1 for these experiments. ABH [2(S)-Amino-6-boronohexanoic acid] was used to inhibit arginase activity. We used Western blotting, immunolabeling, quantitative PCR, and senescence associated β-galactosidase (SA β-Gal) activity to evaluate senescence. Analyses of retinal tissue extracts from diabetic mice showed significant increases in mRNA expression of the senescence-related proteins p16(INK4a), p21, and p53 when compared with non-diabetic mice. SA β-Gal activity and p16(INK4a) immunoreactivity were also increased in retinal vessels from diabetic mice. A1 gene deletion or pharmacological inhibition protected against the induction of premature senescence. A1 overexpression or high glucose treatment increased SA β-Gal activity in cultured ECs. These results demonstrate that A1 is critically involved in diabetes-induced senescence of retinal ECs. Inhibition of arginase activity may therefore be an effective therapeutic strategy to alleviate diabetic retinopathy by preventing premature senescence.
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spelling pubmed-59796102018-06-10 Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1 Shosha, Esraa Xu, Zhimin Narayanan, S. Priya Lemtalsi, Tahira Fouda, Abdelrahman Y. Rojas, Modesto Xing, Ji Fulton, David Caldwell, R. William Caldwell, Ruth B. Int J Mol Sci Article We have recently found that diabetes-induced premature senescence of retinal endothelial cells is accompanied by NOX2-NADPH oxidase-induced increases in the ureohydrolase enzyme arginase 1 (A1). Here, we used genetic strategies to determine the specific involvement of A1 in diabetes-induced endothelial cell senescence. We used A1 knockout mice and wild type mice that were rendered diabetic with streptozotocin and retinal endothelial cells (ECs) exposed to high glucose or transduced with adenovirus to overexpress A1 for these experiments. ABH [2(S)-Amino-6-boronohexanoic acid] was used to inhibit arginase activity. We used Western blotting, immunolabeling, quantitative PCR, and senescence associated β-galactosidase (SA β-Gal) activity to evaluate senescence. Analyses of retinal tissue extracts from diabetic mice showed significant increases in mRNA expression of the senescence-related proteins p16(INK4a), p21, and p53 when compared with non-diabetic mice. SA β-Gal activity and p16(INK4a) immunoreactivity were also increased in retinal vessels from diabetic mice. A1 gene deletion or pharmacological inhibition protected against the induction of premature senescence. A1 overexpression or high glucose treatment increased SA β-Gal activity in cultured ECs. These results demonstrate that A1 is critically involved in diabetes-induced senescence of retinal ECs. Inhibition of arginase activity may therefore be an effective therapeutic strategy to alleviate diabetic retinopathy by preventing premature senescence. MDPI 2018-04-17 /pmc/articles/PMC5979610/ /pubmed/29673160 http://dx.doi.org/10.3390/ijms19041215 Text en © 2018 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
Shosha, Esraa
Xu, Zhimin
Narayanan, S. Priya
Lemtalsi, Tahira
Fouda, Abdelrahman Y.
Rojas, Modesto
Xing, Ji
Fulton, David
Caldwell, R. William
Caldwell, Ruth B.
Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1
title Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1
title_full Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1
title_fullStr Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1
title_full_unstemmed Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1
title_short Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1
title_sort mechanisms of diabetes-induced endothelial cell senescence: role of arginase 1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979610/
https://www.ncbi.nlm.nih.gov/pubmed/29673160
http://dx.doi.org/10.3390/ijms19041215
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