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Functional role of NADPH oxidase isoform 4 (Nox4) in Marfan Syndrome

Grant number: 12/23490-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): April 01, 2013
Effective date (End): March 31, 2014
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal researcher:Francisco Rafael Martins Laurindo
Grantee:Thayna Meirelles Santos
Supervisor abroad: Gustavo Egea
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Research place: Universitat de Barcelona (UB), Spain  


The cardiovascular manifestations, particularly aortic aneurysms are the mainly cause of morbidity and mortality in Marfan syndrome (MS) that is caused by mutations in fibrillin-1 gene. Fibrillin-1 is the main protein of elastic microfibrils. Our PhD project focuses on redox processes study associated with the processing of mutated fibrillin-1 in SM. Data obtained on our in vivo SM investigation demonstrate, for the first time, the involvement of ROS produced by NADPH oxidase in aortic disease progression. ROS production increase in SM is associated with the expression of distinct NAPDH oxidase isoforms, along the temporal evolution of the disease. Nox2 increase is parallel to disease progression in later stages, while Nox4 is increased in the aortas of SM animals independent of age. In addition, we saw a clear association between the aortic phenotype reversion and maintaining higher production of ROS in SM, and worsening aneurysm associated with depletion of these species. These results suggest that ROS may play a protective role in the aorta, analogous to a vaso and cardioprotective effects already described in the literature, on different models. The aim of this project is to investigate the involvement of NADPH oxidase isoform 4 (Nox4) in the development and progression of Marfan Syndrome, by comparing two animal models of SM (with different fibrillin-1 mutations) and knockouts for this protein. Specific Objectives: 1) Develop by successive crosses two animal models Nox4 knockouts with SM with distinct fibrillin-1 mutations; 2) Evaluate the functional role of Nox4 in SM, comparing both models developed. The elucidation of Nox4 involvement in SM, including locating it in signaling pathways mediated by TGF-beta, implicated in disease triggering and progression, can have important therapeutic implications. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MEIRELLES, THAYNA; ARAUJO, THAIS L. S.; NOLASCO, PATRICIA; MORETTI, ANA I. S.; GUIDO, MARIA C.; DEBBAS, VICTOR; PEREIRA, LYGIA V.; LAURINDO, FRANCISCO R. Fibrillin-1 mg Delta(lPn) Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, v. 71, p. 81-91, FEB 2016. Web of Science Citations: 5.

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