Evaluation of the therapeutic potential of Ramipril in a murine model for Marfan syndrome.

• Grant number: 11/00882-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2011
• End date: April 30, 2013
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Bruno Lazzari de Lima
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Marfan syndrome (MFS) is an autosomal dominant disease of connective tissue, which affects 1 in 5,000 individuals. The main clinical manifestations include aneurysms and aortic disruption, excessive growth of bones, scoliosis and thoracic deformities. Mutations in the FBN1 gene, which encodes the fibrillin-1 protein, were genetically linked to the MFS, classifying this disease in the fibrilinopathies group. Studies with animal models for MFS demonstrated that fibrillin-1 alterations leads to an increase in the activity of TGFbeta in tissues, resulting in cardiovascular and pulmonary phenotypes of SMF in those models. Thus, during the last years, therapeutic strategies, based on the use of drugs, have been studied in animal models and patients with MFS. Among these drugs we find the Losartan, an antagonist of AT1, which may restore the vascular and pulmonary phenotype in animal models. Clinical trials involving patients with MFS revealed that, even with the patients presenting improvements in vascular alterations, the results are far from those seen in animal models. The hypothesis is that the dose given to patients is not sufficient to reproduce the effects observed in animals, which received very high drug dose. During the year of 2010 our group evaluated the effect of Ramipril, an ACE inhibitor, on the phenotypic manifestations of SMF in the murine model mg”loxPneo. Treated animals showed an increase of approximately 35% in the FBN1 gene transcription, and a significant improvement in pulmonary and bone manifestation - the last has never been reported in other models for SMF treated with Losartan. Differently of studies involving Losartan, the treatment with Ramipril was realized with doses equivalent to those already used in humans. The objective of this work is a detailed evaluation of the effect of Ramipril on the phenotypic manifestations of the model mg”loxPneo, aiming the understand of the mechanisms related to phenotypic improvement, and thus defining a new therapeutic strategy for the SMF.