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High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy

PURPOSE: Proliferative diabetic retinopathy (PDR) is characterized by retinal new vessel formation, pointing to the importance of the antiangiogenic treatment in PDR. Hepatocyte nuclear factor 4A (HNF4A) has been highlighted to inhibit vascular endothelial growth factor (VEGF)-stimulated in vitro an...

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Autores principales: Yin, Yuan, Wu, Shuai, Niu, Lingzhi, Huang, Shiwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10289276/
https://www.ncbi.nlm.nih.gov/pubmed/37342032
http://dx.doi.org/10.1167/iovs.64.7.32
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author Yin, Yuan
Wu, Shuai
Niu, Lingzhi
Huang, Shiwei
author_facet Yin, Yuan
Wu, Shuai
Niu, Lingzhi
Huang, Shiwei
author_sort Yin, Yuan
collection PubMed
description PURPOSE: Proliferative diabetic retinopathy (PDR) is characterized by retinal new vessel formation, pointing to the importance of the antiangiogenic treatment in PDR. Hepatocyte nuclear factor 4A (HNF4A) has been highlighted to inhibit vascular endothelial growth factor (VEGF)-stimulated in vitro angiogenesis. Therefore, this study aims to elucidate the potential antiangiogenic mechanisms of HNF4A in PDR. METHODS: PDR-related high-throughput sequencing datasets (GSE94019, GSE102485, and GSE191210) were obtained from the Gene Expression Omnibus (GEO) database, followed by the screening of differentially expressed genes (DEGs). The protein-protein interaction (PPI) network of the candidate DEGs was constructed based on gene set enrichment analysis (GSEA) data and Search Tool for the Retrieval of Interacting Genes (STRING) data. In addition, the key genes and pathways related to angiogenesis were screened by functional enrichment analysis. Furthermore, human retinal microvascular cells were used for further in vitro validation. RESULTS: Four key genes (CACNA1A, CACNA1E, PDE1B, and CHRM3) related to PDR were identified in the grey module. CACNA1A affected angiogenesis in PDR by regulating vascular endothelial growth factor A (VEGFA) expression. Furthermore, HNF4A participated in angiogenesis in PDR by activating CACNA1A. In vitro experiments further identified that inhibition of HNF4A reduced CACNA1A expression and increased VEGFA expression, thus promoting angiogenesis in PDR. CONCLUSIONS: In conclusion, the obtained findings suggest that antiangiogenic HNF4A activates the CACNA1A/VEGFA axis in PDR. Our work provides new insights into the angiogenic mechanism of PDR and offers potential targets for translational applications.
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spelling pubmed-102892762023-06-24 High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy Yin, Yuan Wu, Shuai Niu, Lingzhi Huang, Shiwei Invest Ophthalmol Vis Sci Immunology and Microbiology PURPOSE: Proliferative diabetic retinopathy (PDR) is characterized by retinal new vessel formation, pointing to the importance of the antiangiogenic treatment in PDR. Hepatocyte nuclear factor 4A (HNF4A) has been highlighted to inhibit vascular endothelial growth factor (VEGF)-stimulated in vitro angiogenesis. Therefore, this study aims to elucidate the potential antiangiogenic mechanisms of HNF4A in PDR. METHODS: PDR-related high-throughput sequencing datasets (GSE94019, GSE102485, and GSE191210) were obtained from the Gene Expression Omnibus (GEO) database, followed by the screening of differentially expressed genes (DEGs). The protein-protein interaction (PPI) network of the candidate DEGs was constructed based on gene set enrichment analysis (GSEA) data and Search Tool for the Retrieval of Interacting Genes (STRING) data. In addition, the key genes and pathways related to angiogenesis were screened by functional enrichment analysis. Furthermore, human retinal microvascular cells were used for further in vitro validation. RESULTS: Four key genes (CACNA1A, CACNA1E, PDE1B, and CHRM3) related to PDR were identified in the grey module. CACNA1A affected angiogenesis in PDR by regulating vascular endothelial growth factor A (VEGFA) expression. Furthermore, HNF4A participated in angiogenesis in PDR by activating CACNA1A. In vitro experiments further identified that inhibition of HNF4A reduced CACNA1A expression and increased VEGFA expression, thus promoting angiogenesis in PDR. CONCLUSIONS: In conclusion, the obtained findings suggest that antiangiogenic HNF4A activates the CACNA1A/VEGFA axis in PDR. Our work provides new insights into the angiogenic mechanism of PDR and offers potential targets for translational applications. The Association for Research in Vision and Ophthalmology 2023-06-21 /pmc/articles/PMC10289276/ /pubmed/37342032 http://dx.doi.org/10.1167/iovs.64.7.32 Text en Copyright 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Immunology and Microbiology
Yin, Yuan
Wu, Shuai
Niu, Lingzhi
Huang, Shiwei
High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy
title High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy
title_full High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy
title_fullStr High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy
title_full_unstemmed High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy
title_short High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy
title_sort high-throughput sequencing data reveal an antiangiogenic role of hnf4a-mediated cacna1a/vegfa axis in proliferative diabetic retinopathy
topic Immunology and Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10289276/
https://www.ncbi.nlm.nih.gov/pubmed/37342032
http://dx.doi.org/10.1167/iovs.64.7.32
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