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Protein Disulfide Isomerase (PDI)-A1 peri/epicellular: a new therapeutic target in Aortic Aneurysm

Grant number: 17/11410-6
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2017
Effective date (End): September 30, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Francisco Rafael Martins Laurindo
Grantee:Fernando Garcez Porto
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
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

Vascular aneurysms constitute a type of exacerbated expansive remodeling, in which the greatest point of degradation occurs in the external part of the vessel, causing high morbidity and mortality and constituting a therapeutic need not contemplated. Mechanisms that coordinate vascular remodeling involve mechanoadaptation processes and our group has shown evidence that redox signaling pathways regulate such processes. In particular, dithiol-proteins from the disulfide isomerase family of proteins (PDIs), from the thioredoxin superfamily, have an effect on redox regulation of the cytoskeleton and extracellular matrix. We have shown that the extracellular fraction of PDIA1 (PDI epi/pericellular or pecPDI) contributes to expansive remodeling of the vessel during vascular repair. We postulate that pecPDI contributes to the pathophysiology of Aortic Aneurysms. Our objective is to investigate the effect of pecPDI inhibition on two models of Aortic, Thoracic and Abdominal Aneurysms, caused by distinct pathophysiological mechanisms, exploring possible redox pathways involved in this process. The specific objectives are: 1) to validate in our model the pharmacological inhibition of pecPDI with flavonoid compounds widely documented in the literature. To assess the effects of these inhibitors on the progression of the C57BL/6 induced thoracic aortic aneurysm by the lysyl-oxidasebeta-aminopropionitrile inhibitor (BAPN), evaluating in vivo echocardiographic changes, histopathological structure, viscoelastic properties and expression of matrix metalloproteinases; 2) to study the effects of pharmacological inhibition of pecPDI on the progression of Abdominal Aortic Aneurysm, analyzing the same variables investigated in the objective (1); 3) to explore, in a selected model in objectives (1) and (2), mechanisms involved in Aneurysm development and response to treatment, focusing on the study of the production of oxidants and thiol-disulfide equilibrium; expression and activation of Nrf2 and its secondary targets; expression of specific NADPH oxidases; modulation of integrins. These results have the potential to show mechanisms relevant to the genesis of the Aneurysm and generate data of potential preclinical relevance. (AU)