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An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a m...

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Autores principales: Bhushan, Raghu, Altinbas, Lukas, Jäger, Marten, Zaradzki, Marcin, Lehmann, Daniel, Timmermann, Bernd, Clayton, Nicholas P., Zhu, Yunxiang, Kallenbach, Klaus, Kararigas, Georgios, Robinson, Peter N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433740/
https://www.ncbi.nlm.nih.gov/pubmed/30677223
http://dx.doi.org/10.1111/jcmm.14137
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author Bhushan, Raghu
Altinbas, Lukas
Jäger, Marten
Zaradzki, Marcin
Lehmann, Daniel
Timmermann, Bernd
Clayton, Nicholas P.
Zhu, Yunxiang
Kallenbach, Klaus
Kararigas, Georgios
Robinson, Peter N.
author_facet Bhushan, Raghu
Altinbas, Lukas
Jäger, Marten
Zaradzki, Marcin
Lehmann, Daniel
Timmermann, Bernd
Clayton, Nicholas P.
Zhu, Yunxiang
Kallenbach, Klaus
Kararigas, Georgios
Robinson, Peter N.
author_sort Bhushan, Raghu
collection PubMed
description Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS. We performed RNA‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type (WT) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS‐related pathology. Among these, we identified Igfbp2, Ccl8, Spp1, Mylk2, Mfap4, Dsp and H19. We confirmed the expression of regulated genes by quantitative real‐time PCR. Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pSmad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS.
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spelling pubmed-64337402019-04-08 An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology Bhushan, Raghu Altinbas, Lukas Jäger, Marten Zaradzki, Marcin Lehmann, Daniel Timmermann, Bernd Clayton, Nicholas P. Zhu, Yunxiang Kallenbach, Klaus Kararigas, Georgios Robinson, Peter N. J Cell Mol Med Original Articles Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS‐related mortality. Aberrant TGF‐beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS. We performed RNA‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type (WT) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS‐related pathology. Among these, we identified Igfbp2, Ccl8, Spp1, Mylk2, Mfap4, Dsp and H19. We confirmed the expression of regulated genes by quantitative real‐time PCR. Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pSmad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS. John Wiley and Sons Inc. 2019-01-24 2019-04 /pmc/articles/PMC6433740/ /pubmed/30677223 http://dx.doi.org/10.1111/jcmm.14137 Text en © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Bhushan, Raghu
Altinbas, Lukas
Jäger, Marten
Zaradzki, Marcin
Lehmann, Daniel
Timmermann, Bernd
Clayton, Nicholas P.
Zhu, Yunxiang
Kallenbach, Klaus
Kararigas, Georgios
Robinson, Peter N.
An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
title An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
title_full An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
title_fullStr An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
title_full_unstemmed An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
title_short An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology
title_sort integrative systems approach identifies novel candidates in marfan syndrome‐related pathophysiology
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433740/
https://www.ncbi.nlm.nih.gov/pubmed/30677223
http://dx.doi.org/10.1111/jcmm.14137
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