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Effects of the inhibition of the angiotensin converting enzyme in osteogenic differentiation of induced pluripotent stem cells (iPSCs) derived from patients with Marfan Syndrome

Grant number: 14/01296-3
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2014
Effective date (End): December 31, 2014
Field of knowledge:Biological Sciences - Biology
Principal Investigator:Lygia da Veiga Pereira
Grantee:Juliana Borsoi Sant'Ana
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Marfan Syndrome (MFS) is an autossomal dominant connective tissue disorder that affects about 1 in 5,000 individuals. The main clinical manifestations include aneurysms and aortic rupture, bone overgrowth, scoliosis and thoracic deformities. MFS is caused by mutations in the FBN1 gene encoding the extracellular matrix protein fibrillin-1, the major structural component of the microfibrils that comprise the elastic fibers. Recently, it was demonstrated that fibrillin-1 is important in the modulation of the bioavailability of the transforming growth factor -beta (TGF-beta). In animal models, it was observed that mutations in fibrillin-1 lead to an increased activity of TGF-beta in tissues, which in turn leads to the cardiovascular and pulmonary phenotypes of the syndrome. Evidences show the involvement of the renin-angiotensin system (RAS) in TGF-beta signalling and therapeutic strategies based on the use of drugs that interfere in this system have been studied in animal models and patients with MFS. Among these drugs, stands out Losartan, an antagonist of the type I receptor of angiotensin II (AT-1) capable of reversing the vascular and pulmonary phenotypes in animal models, but not the bone phenotype. However, it was also demonstrated that RAS perform an important role in bone metabolism. In vitro experiments with induced pluripotent stem cells (iPSCs) derived from patients with MFS showed absence of osteogenic differentiation, reduction in the expression of many osteogenic markers and increased TGF-beta signalling in these cells. Therefore, the aim of this study is to evaluate the effect of Ramipril and Enalapril, two angiotensin converting enzyme (ACE) inhibitors, in the osteogenic differentiation of iPSCs derived from patients with MFS. (AU)

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