Mechanisms and implications of the mTORC1 signaling pathway in the cardiovascular phenotype of Marfan Syndrome

• Grant number: 14/24511-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): June 01, 2015
• Effective date (End): May 31, 2019
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Patricia Nolasco Santos
• Host 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

Abstract

The Marfan syndrome (SMF), caused by mutations in the fibrillin-1 gene elastic matrix, whose main phenotype aortic aneurysms, valvular heart disease and cardiomyopathy. Several mechanisms are linked to the pathophysiology of SMF, especially signaling via angiotensin AT1 receptor, TGF-² and its non-canonical pathway involving the kinase ERK. Studies from our group indicate that redox pathways may have a protective role paradoxically, treatment of mice with mg”loxpneo mutation of fibrillin-1 with the antioxidant lipoic acid (LA) induced aggravation of cardiovascular phenotype despite the inhibition of ERK. We postulate that LA induces a collateral pathway to ERK able to sustain the vascular phenotype. Understanding the way in which amplification AL modulates the phenotype of the disease despite the inhibition of ERK may provide alternative methods of treatment of disease. Published data suggest activation of the mTOR pathway by AL. Our hypothesis is that the path of mTORC1 complex may contribute to the phenotype of the SMF and potentially be a failure mechanism / reduction therapeutic response to the AT1 receptor inhibitors without exposure AL. The goal of the project is to investigate the profile of activation and expression of the mTORC1 complex and via ERK signaling in two major murine models of SMF (mg”loxpneo and C1039G). In these models, we will investigate the effect of treatment with rapamycin mTORC1 inhibitor in phenotype SMF cardiovascular (aorta / heart), and by histology and echocardiogram to assess the activity of matrix metalloproteinases. Moreover, VSMC isolated from SMF with C57BI6 mice, we will investigate the activation and expression induced AL mTORC1 complex mechanistic pathways and possible associated. These results may have significant translational implications. (AU)

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)

MORETTI, ANA I. S.; PAVANELLI, JESSYCA C.; NOLASCO, PATRICIA; LEISEGANG, MATTHIAS S.; TANAKA, LEONARDO Y.; FERNANDES, CAROLINA G.; WOSNIAK, JR., JOAO; KAJIHARA, DANIELA; DIAS, MATHEUS H.; FERNANDES, DENISE C.; et al. Conserved Gene Microsynteny Unveils Functional Interaction Between Protein Disulfide Isomerase and Rho Guanine-Dissociation Inhibitor Families. SCIENTIFIC REPORTS, v. 7, DEC 8 2017. (09/54764-6, 15/15281-0, 12/10203-3, 14/24511-7, 13/07937-8)

NOLASCO, PATRICIA; FERNANDES, CAROLINA GONCALVES; RIBEIRO-SILVA, JOAO CARLOS; OLIVEIRA, PERCILLIA V. S.; SACRINI, MARIANA; DE BRITO, ISIS VASCONCELOS; DE BESSA, TIPHANY CORALIE; PEREIRA, LYGIA V.; TANAKA, LEONARDO Y.; ALENCAR, ADRIANO; et al. Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1866, n. 1, JAN 1 2020. (18/07230-5, 14/24511-7, 13/07937-8, 14/20595-1)

KOWALTOWSKI, ALICIA J.; MENEZES-FILHO, SERGIO L.; ASSALI, ESSAM A.; GONCALVES, ISABELA G.; CABRAL-COSTA, JOAO VICTOR; ABREU, PHABLO; MILLER, NATHANAEL; NOLASCO, PATRICIA; LAURINDO, FRANCISCO R. M.; BRUNI-CARDOSO, ALEXANDRE; et al. Mitochondrial morphology regulates organellar Ca2+ uptake and changes cellular Ca2+ homeostasis. FASEB JOURNAL, v. 33, n. 12, p. 13176-13188, DEC 2019. (16/18633-8, 14/24511-7, 13/07937-8, 17/14713-0)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SANTOS, Patricia Nolasco. Correlation between the VSMC mechanobiology with phenotypic reprogramming and exacerbated responses to stress in Marfan syndrome cardiovascular phenotype. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.