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.

• Authors: Jasmin Wellbrock, Sara Sheikhzadeh, Leticia Oliveira-Ferrer, Hauke Stamm, Mathias Hillebrand, Britta Keyser, Marianne Klokow, Gabi Vohwinkel, Veronika Bonk, Benjamin Otto, Thomas Streichert, Stefan Balabanov, Christian Hagel, Meike Rybczynski, Frank Bentzien, Carsten Bokemeyer, Yskert von Kodolitsch, Walter Fiedler
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e104742 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25116393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMP2 protein, human
• BMP4 protein, human
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Protein 4
• GREM1 protein, human
• Intercellular Signaling Peptides and Proteins
• LTBP1 protein, human
• Latent TGF-beta Binding Proteins
• RNA, Messenger
• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• BMPR1A protein, human
• Bone Morphogenetic Protein Receptors, Type I
• Receptor, Transforming Growth Factor-beta Type I
• Receptor, Transforming Growth Factor-beta Type II
• TGFBR1 protein, human

Topics

• Adult
• Aorta (metabolism, pathology)
• Bone Morphogenetic Protein 2 (biosynthesis, genetics)
• Bone Morphogenetic Protein 4 (biosynthesis, genetics)
• Bone Morphogenetic Protein Receptors, Type I (biosynthesis, genetics)
• Cell Proliferation (genetics)
• Early Diagnosis
• Endothelial Cells (pathology)
• Female
• Gene Expression Profiling
• Humans
• Intercellular Signaling Peptides and Proteins (biosynthesis)
• Latent TGF-beta Binding Proteins (biosynthesis)
• Loeys-Dietz Syndrome (diagnosis, genetics, physiopathology)
• Male
• Middle Aged
• Muscle, Smooth, Vascular (metabolism)
• Protein Serine-Threonine Kinases (genetics)
• RNA, Messenger (biosynthesis)
• Receptor, Transforming Growth Factor-beta Type I
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (genetics)
• Young Adult