Fibulin-4 deficiency increases TGF-beta signalling in aortic smooth muscle cells due to elevated TGF-beta 2 levels
| Autor: | L. te Riet, Ahj Danser, Madelon Paauwe, P. ten Dijke, Marcel Vermeij, P.M. van Heijningen, Natasja W. M. Ramnath, Roland Kanaar, Lukas J. A. C. Hawinkels, Jeroen Essers |
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| Přispěvatelé: | Surgery, Molecular Genetics, Pathology, Internal Medicine, Radiotherapy |
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Myocytes Smooth Muscle Aorta Thoracic Real-Time Polymerase Chain Reaction Article Transforming Growth Factor beta1 Pathogenesis Transforming Growth Factor beta2 Aortic aneurysm Downregulation and upregulation medicine.artery Internal medicine Human Umbilical Vein Endothelial Cells medicine Animals Humans Myocyte Receptor Aorta Cell Proliferation Extracellular Matrix Proteins Multidisciplinary Chemistry Anatomy medicine.disease Fibulin Mice Inbred C57BL Endocrinology cardiovascular system Signal transduction Signal Transduction |
| Zdroj: | Scientific Reports, 5. Nature Publishing Group Scientific Reports, 5 Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Fibulins are extracellular matrix proteins associated with elastic fibres. Homozygous Fibulin-4 mutations lead to life-threatening abnormalities such as aortic aneurysms. Aortic aneurysms in Fibulin-4 mutant mice were associated with upregulation of TGF-β signalling. How Fibulin-4 deficiency leads to deregulation of the TGF-β pathway is largely unknown. Isolated aortic smooth muscle cells (SMCs) from Fibulin-4 deficient mice showed reduced growth, which could be reversed by treatment with TGF-β neutralizing antibodies. In Fibulin-4 deficient SMCs increased TGF-β signalling was detected using a transcriptional reporter assay and by increased SMAD2 phosphorylation. Next, we investigated if the increased activity was due to increased levels of the three TGF-β isoforms. These data revealed slightly increased TGF-β1 and markedly increased TGF-β2 levels. Significantly increased TGF-β2 levels were also detectable in plasma from homozygous Fibulin-4R/R mice, not in wild type mice. TGF-β2 levels were reduced after losartan treatment, an angiotensin-II type-1 receptor blocker, known to prevent aortic aneurysm formation. In conclusion, we have shown increased TGF-β signalling in isolated SMCs from Fibulin-4 deficient mouse aortas, not only caused by increased levels of TGF-β1, but especially TGF-β2. These data provide new insights in the molecular interaction between Fibulin-4 and TGF-β pathway regulation in the pathogenesis of aortic aneurysms. |
| Databáze: | OpenAIRE |
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