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Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PAH patients remains low. There is thus an important need to identify nove...

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Autores principales: Sasagawa, Shota, Nishimura, Yuhei, Sawada, Hirofumi, Zhang, Erquan, Okabe, Shiko, Murakami, Soichiro, Ashikawa, Yoshifumi, Yuge, Mizuki, Kawaguchi, Koki, Kawase, Reiko, Mitani, Yoshihide, Maruyama, Kazuo, Tanaka, Toshio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894905/
https://www.ncbi.nlm.nih.gov/pubmed/27375481
http://dx.doi.org/10.3389/fphar.2016.00142
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author Sasagawa, Shota
Nishimura, Yuhei
Sawada, Hirofumi
Zhang, Erquan
Okabe, Shiko
Murakami, Soichiro
Ashikawa, Yoshifumi
Yuge, Mizuki
Kawaguchi, Koki
Kawase, Reiko
Mitani, Yoshihide
Maruyama, Kazuo
Tanaka, Toshio
author_facet Sasagawa, Shota
Nishimura, Yuhei
Sawada, Hirofumi
Zhang, Erquan
Okabe, Shiko
Murakami, Soichiro
Ashikawa, Yoshifumi
Yuge, Mizuki
Kawaguchi, Koki
Kawase, Reiko
Mitani, Yoshihide
Maruyama, Kazuo
Tanaka, Toshio
author_sort Sasagawa, Shota
collection PubMed
description Pulmonary arterial hypertension (PAH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PAH patients remains low. There is thus an important need to identify novel genes that are commonly dysregulated in PAH of various etiologies and could be used as biomarkers and/or therapeutic targets. In this study, we performed comparative transcriptome analysis of five mammalian PAH datasets downloaded from a public database. We identified 228 differentially expressed genes (DEGs) from a rat PAH model caused by inhibition of vascular endothelial growth factor receptor under hypoxic conditions, 379 DEGs from a mouse PAH model associated with systemic sclerosis, 850 DEGs from a mouse PAH model associated with schistosomiasis, 1598 DEGs from one cohort of human PAH patients, and 4260 DEGs from a second cohort of human PAH patients. Gene-by-gene comparison identified four genes that were differentially upregulated or downregulated in parallel in all five sets of DEGs. Expression of coiled-coil domain containing 80 (CCDC80) and anterior gradient two genes was significantly increased in the five datasets, whereas expression of SMAD family member six and granzyme A was significantly decreased. Weighted gene co-expression network analysis revealed a connection between CCDC80 and collagen type I alpha 1 (COL1A1) expression. To validate the function of CCDC80 in vivo, we knocked out ccdc80 in zebrafish using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. In vivo imaging of zebrafish expressing a fluorescent protein in endothelial cells showed that ccdc80 deletion significantly increased the diameter of the ventral artery, a vessel supplying blood to the gills. We also demonstrated that expression of col1a1 and endothelin-1 mRNA was significantly decreased in the ccdc80-knockout zebrafish. Finally, we examined Ccdc80 immunoreactivity in a rat PAHmodel and found increased expression in the hypertrophied media and adventitia of the pre-acinar pulmonary arteries (PAs) and in the thickened intima, media, and adventitia of the obstructed intra-acinar PAs. These results suggest that increased expression of CCDC80 may be involved in the pathogenesis of PAH, potentially by modulating the expression of endothelin-1 and COL1A1.
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spelling pubmed-48949052016-07-01 Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension Sasagawa, Shota Nishimura, Yuhei Sawada, Hirofumi Zhang, Erquan Okabe, Shiko Murakami, Soichiro Ashikawa, Yoshifumi Yuge, Mizuki Kawaguchi, Koki Kawase, Reiko Mitani, Yoshihide Maruyama, Kazuo Tanaka, Toshio Front Pharmacol Pharmacology Pulmonary arterial hypertension (PAH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PAH patients remains low. There is thus an important need to identify novel genes that are commonly dysregulated in PAH of various etiologies and could be used as biomarkers and/or therapeutic targets. In this study, we performed comparative transcriptome analysis of five mammalian PAH datasets downloaded from a public database. We identified 228 differentially expressed genes (DEGs) from a rat PAH model caused by inhibition of vascular endothelial growth factor receptor under hypoxic conditions, 379 DEGs from a mouse PAH model associated with systemic sclerosis, 850 DEGs from a mouse PAH model associated with schistosomiasis, 1598 DEGs from one cohort of human PAH patients, and 4260 DEGs from a second cohort of human PAH patients. Gene-by-gene comparison identified four genes that were differentially upregulated or downregulated in parallel in all five sets of DEGs. Expression of coiled-coil domain containing 80 (CCDC80) and anterior gradient two genes was significantly increased in the five datasets, whereas expression of SMAD family member six and granzyme A was significantly decreased. Weighted gene co-expression network analysis revealed a connection between CCDC80 and collagen type I alpha 1 (COL1A1) expression. To validate the function of CCDC80 in vivo, we knocked out ccdc80 in zebrafish using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. In vivo imaging of zebrafish expressing a fluorescent protein in endothelial cells showed that ccdc80 deletion significantly increased the diameter of the ventral artery, a vessel supplying blood to the gills. We also demonstrated that expression of col1a1 and endothelin-1 mRNA was significantly decreased in the ccdc80-knockout zebrafish. Finally, we examined Ccdc80 immunoreactivity in a rat PAHmodel and found increased expression in the hypertrophied media and adventitia of the pre-acinar pulmonary arteries (PAs) and in the thickened intima, media, and adventitia of the obstructed intra-acinar PAs. These results suggest that increased expression of CCDC80 may be involved in the pathogenesis of PAH, potentially by modulating the expression of endothelin-1 and COL1A1. Frontiers Media S.A. 2016-06-07 /pmc/articles/PMC4894905/ /pubmed/27375481 http://dx.doi.org/10.3389/fphar.2016.00142 Text en Copyright © 2016 Sasagawa, Nishimura, Sawada, Zhang, Okabe, Murakami, Ashikawa, Yuge, Kawaguchi, Kawase, Mitani, Maruyama and Tanaka. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sasagawa, Shota
Nishimura, Yuhei
Sawada, Hirofumi
Zhang, Erquan
Okabe, Shiko
Murakami, Soichiro
Ashikawa, Yoshifumi
Yuge, Mizuki
Kawaguchi, Koki
Kawase, Reiko
Mitani, Yoshihide
Maruyama, Kazuo
Tanaka, Toshio
Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension
title Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension
title_full Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension
title_fullStr Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension
title_full_unstemmed Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension
title_short Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension
title_sort comparative transcriptome analysis identifies ccdc80 as a novel gene associated with pulmonary arterial hypertension
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894905/
https://www.ncbi.nlm.nih.gov/pubmed/27375481
http://dx.doi.org/10.3389/fphar.2016.00142
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