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Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)

Period 2-mutant mice (Per2(m/m)), which possess a circadian dysfunction, recapitulate the retinal vascular phenotype similar to diabetic retinopathy (DR). The vascular dysfunction in Per2(m/m) is associated with an increase in connective tissue growth factor (CTGF/CCN2). At the molecular level, CTGF...

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Autores principales: Jadhav, Vaishnavi, Luo, Qianyi, M. Dominguez, James, Al-Sabah, Jude, Chaqour, Brahim, Grant, Maria B., Bhatwadekar, Ashay D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035004/
https://www.ncbi.nlm.nih.gov/pubmed/27662578
http://dx.doi.org/10.1371/journal.pone.0163367
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author Jadhav, Vaishnavi
Luo, Qianyi
M. Dominguez, James
Al-Sabah, Jude
Chaqour, Brahim
Grant, Maria B.
Bhatwadekar, Ashay D.
author_facet Jadhav, Vaishnavi
Luo, Qianyi
M. Dominguez, James
Al-Sabah, Jude
Chaqour, Brahim
Grant, Maria B.
Bhatwadekar, Ashay D.
author_sort Jadhav, Vaishnavi
collection PubMed
description Period 2-mutant mice (Per2(m/m)), which possess a circadian dysfunction, recapitulate the retinal vascular phenotype similar to diabetic retinopathy (DR). The vascular dysfunction in Per2(m/m) is associated with an increase in connective tissue growth factor (CTGF/CCN2). At the molecular level, CTGF gene expression is dependent on the canonical Wnt/β-catenin pathway. The nuclear binding of β-catenin to a transcription factor, lymphoid enhancer binding protein (Lef)/ T-cell factor (TCF/LEF), leads to downstream activation of CTGF. For this study, we hypothesized that the silencing of Per2 results in nuclear translocation and subsequent transactivation of the CTGF gene. To test this hypothesis, we performed immunofluorescence labeling for CTGF in retinal sections from wild-type (WT) and Per2(m/m) mice. Human retinal endothelial cells (HRECs) were transfected with siRNA for Per2, and the protein expression of CTGF and β-catenin was evaluated. The TCF/LEF luciferase reporter (TOPflash) assay was performed to validate the involvement of β-catenin in the activation of CTGF. Per2(m/m) retinas exhibited an increased CTGF immunostaining in ganglion cell layer and retinal endothelium. Silencing of Per2 using siRNA resulted in an upregulation of CTGF and β-catenin. The TOPflash assay revealed an increase in luminescence for HRECs transfected with Per2 siRNA. Our studies show that loss of Per2 results in an activation of CTGF via nuclear entry of β-catenin. Our study provides novel insight into the understanding of microvascular dysfunction in Per2(m/m) mice.
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spelling pubmed-50350042016-10-10 Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF) Jadhav, Vaishnavi Luo, Qianyi M. Dominguez, James Al-Sabah, Jude Chaqour, Brahim Grant, Maria B. Bhatwadekar, Ashay D. PLoS One Research Article Period 2-mutant mice (Per2(m/m)), which possess a circadian dysfunction, recapitulate the retinal vascular phenotype similar to diabetic retinopathy (DR). The vascular dysfunction in Per2(m/m) is associated with an increase in connective tissue growth factor (CTGF/CCN2). At the molecular level, CTGF gene expression is dependent on the canonical Wnt/β-catenin pathway. The nuclear binding of β-catenin to a transcription factor, lymphoid enhancer binding protein (Lef)/ T-cell factor (TCF/LEF), leads to downstream activation of CTGF. For this study, we hypothesized that the silencing of Per2 results in nuclear translocation and subsequent transactivation of the CTGF gene. To test this hypothesis, we performed immunofluorescence labeling for CTGF in retinal sections from wild-type (WT) and Per2(m/m) mice. Human retinal endothelial cells (HRECs) were transfected with siRNA for Per2, and the protein expression of CTGF and β-catenin was evaluated. The TCF/LEF luciferase reporter (TOPflash) assay was performed to validate the involvement of β-catenin in the activation of CTGF. Per2(m/m) retinas exhibited an increased CTGF immunostaining in ganglion cell layer and retinal endothelium. Silencing of Per2 using siRNA resulted in an upregulation of CTGF and β-catenin. The TOPflash assay revealed an increase in luminescence for HRECs transfected with Per2 siRNA. Our studies show that loss of Per2 results in an activation of CTGF via nuclear entry of β-catenin. Our study provides novel insight into the understanding of microvascular dysfunction in Per2(m/m) mice. Public Library of Science 2016-09-23 /pmc/articles/PMC5035004/ /pubmed/27662578 http://dx.doi.org/10.1371/journal.pone.0163367 Text en © 2016 Jadhav et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jadhav, Vaishnavi
Luo, Qianyi
M. Dominguez, James
Al-Sabah, Jude
Chaqour, Brahim
Grant, Maria B.
Bhatwadekar, Ashay D.
Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)
title Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)
title_full Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)
title_fullStr Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)
title_full_unstemmed Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)
title_short Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)
title_sort per2-mediated vascular dysfunction is caused by the upregulation of the connective tissue growth factor (ctgf)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035004/
https://www.ncbi.nlm.nih.gov/pubmed/27662578
http://dx.doi.org/10.1371/journal.pone.0163367
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