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Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection

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Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection. / Wellbrock, Jasmin; Sheikhzadeh, Sara; Oliveira Ferrer, Leticia; Stamm, Hauke; Hillebrand, Mathias; Keyser, Britta; Klokow, Marianne; Vohwinkel, Gabi; Bonk, Veronika; Otto, Benjamin; Streichert, Thomas; Balabanov, Stefan; Hagel, Christian; Rybczynski, Meike; Bentzien, Frank; Bokemeyer, Carsten; Kodolitsch, Yskert; Fiedler, Walter.

In: PLOS ONE, Vol. 9, No. 8, 01.01.2014, p. e104742.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Wellbrock, J, Sheikhzadeh, S, Oliveira Ferrer, L, Stamm, H, Hillebrand, M, Keyser, B, Klokow, M, Vohwinkel, G, Bonk, V, Otto, B, Streichert, T, Balabanov, S, Hagel, C, Rybczynski, M, Bentzien, F, Bokemeyer, C, Kodolitsch, Y & Fiedler, W 2014, 'Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection', PLOS ONE, vol. 9, no. 8, pp. e104742. https://doi.org/10.1371/journal.pone.0104742

APA

Wellbrock, J., Sheikhzadeh, S., Oliveira Ferrer, L., Stamm, H., Hillebrand, M., Keyser, B., Klokow, M., Vohwinkel, G., Bonk, V., Otto, B., Streichert, T., Balabanov, S., Hagel, C., Rybczynski, M., Bentzien, F., Bokemeyer, C., Kodolitsch, Y., & Fiedler, W. (2014). Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection. PLOS ONE, 9(8), e104742. https://doi.org/10.1371/journal.pone.0104742

Vancouver

Wellbrock J, Sheikhzadeh S, Oliveira Ferrer L, Stamm H, Hillebrand M, Keyser B et al. Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection. PLOS ONE. 2014 Jan 1;9(8):e104742. https://doi.org/10.1371/journal.pone.0104742

Bibtex

@article{661ad82900a84f75be9d23b8bd7f4af3,
title = "Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection",
abstract = "BACKGROUNDS: The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor β (TGF-β) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-β receptor mutations.METHODS AND RESULTS: We performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-β pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects.CONCLUSIONS: These findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.",
author = "Jasmin Wellbrock and Sara Sheikhzadeh and {Oliveira Ferrer}, Leticia and Hauke Stamm and Mathias Hillebrand and Britta Keyser and Marianne Klokow and Gabi Vohwinkel and Veronika Bonk and Benjamin Otto and Thomas Streichert and Stefan Balabanov and Christian Hagel and Meike Rybczynski and Frank Bentzien and Carsten Bokemeyer and Yskert Kodolitsch and Walter Fiedler",
year = "2014",
month = jan,
day = "1",
doi = "10.1371/journal.pone.0104742",
language = "English",
volume = "9",
pages = "e104742",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

RIS

TY - JOUR

T1 - Overexpression of Gremlin-1 in Patients with Loeys-Dietz Syndrome: Implications on Pathophysiology and Early Disease Detection

AU - Wellbrock, Jasmin

AU - Sheikhzadeh, Sara

AU - Oliveira Ferrer, Leticia

AU - Stamm, Hauke

AU - Hillebrand, Mathias

AU - Keyser, Britta

AU - Klokow, Marianne

AU - Vohwinkel, Gabi

AU - Bonk, Veronika

AU - Otto, Benjamin

AU - Streichert, Thomas

AU - Balabanov, Stefan

AU - Hagel, Christian

AU - Rybczynski, Meike

AU - Bentzien, Frank

AU - Bokemeyer, Carsten

AU - Kodolitsch, Yskert

AU - Fiedler, Walter

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BACKGROUNDS: The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor β (TGF-β) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-β receptor mutations.METHODS AND RESULTS: We performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-β pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects.CONCLUSIONS: These findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.

AB - BACKGROUNDS: The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor β (TGF-β) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-β receptor mutations.METHODS AND RESULTS: We performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-β pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects.CONCLUSIONS: These findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.

U2 - 10.1371/journal.pone.0104742

DO - 10.1371/journal.pone.0104742

M3 - SCORING: Journal article

C2 - 25116393

VL - 9

SP - e104742

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 8

ER -