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

• Published in: PloS one Vol. 9; no. 8; p. e104742
• Main Authors: 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, von Kodolitsch, Yskert, Fiedler, Walter
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.08.2014; Public Library of Science (PLoS)
• Subjects: Adult; Aorta; Aorta - metabolism; Aorta - pathology; Biology and Life Sciences; Blood circulation; Bone marrow; Bone morphogenetic protein 2; Bone Morphogenetic Protein 2 - biosynthesis; Bone Morphogenetic Protein 2 - genetics; Bone morphogenetic protein 4; Bone Morphogenetic Protein 4 - biosynthesis; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein Receptors, Type I - biosynthesis; Bone Morphogenetic Protein Receptors, Type I - genetics; Cancer; Cardiology; Cell Proliferation - genetics; Connective tissues; Coronary vessels; Diagnostic systems; Disease detection; DNA microarrays; Early Diagnosis; Endothelial cells; Endothelial Cells - pathology; Female; Gene expression; Gene Expression Profiling; Gremlin protein; Growth factors; Heart surgery; Hematology; Humans; Immunoblotting; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - biosynthesis; Kinases; Laboratories; Latent TGF-beta Binding Proteins - biosynthesis; Loeys-Dietz Syndrome - diagnosis; Loeys-Dietz Syndrome - genetics; Loeys-Dietz Syndrome - physiopathology; Male; Medicine and Health Sciences; Middle Aged; Muscle, Smooth, Vascular - metabolism; Muscles; Mutation; Oncology; Pathogenesis; Patients; Peripheral blood; Plasma levels; Protein-Serine-Threonine Kinases - genetics; Proteins; Pulmonary hypertension; Receptors; Receptors, Transforming Growth Factor beta - genetics; RNA, Messenger - biosynthesis; Signal transduction; Signaling; Smooth muscle; Surgery; Transforming growth factor-b; Young Adult; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104742

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. 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. 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.