Temporal analysis of Protein Disulfide Isomerase and Enolase-1 expressions in the development of experimental aortic aneurysm

• Grant number: 25/07629-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Amanda Silva Aguilar
• 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
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

Aortic disease, including aneurysm and dissection of the vascular wall, involves aberrant remodeling of the vessel, characterized by predominant degradation of the outer layer. Aortic disease carries high rates of morbidity and mortality and represents a therapeutic challenge yet to be addressed. The pathophysiology of aortic disease involves mechanisms of mechanical adaptation, in which redox processes are involved. Our group has extensively characterized the effects of thiol redox chaperones of the "Protein Disulfide Isomerases" (PDIs) family on the redox modulation of the cytoskeleton and extracellular matrix. Genetic overexpression of PDIA1, the prototype of the PDI family, is protective against aortic dissection in mice. However, the mechanism of the protective effects of PDIA1 is unknown. PDIA1 interacts with enolase-1 (ENO-1), a glycolytic enzyme that has non-canonical effects on extracellular proteolysis, e.g., as a plasminogen receptor. Our hypothesis is that the interaction with ENO-1 is a mechanism involved in the protection against aortic disease by PDIA1. This hypothesis is being addressed in studies by the group using mouse models of aortic disease induced by the administration of BAPN, a lysyl oxidase inhibitor that prevents elastogenesis, resulting in aortic dilation and rupture. The present project seeks to extend these studies, aiming to evaluate the temporal evolution of PDIA1 and ENO1 expressions in the different layers of the vessel, at different times after BAPN administration. In addition, aortic disease affects different topographies of the vessel differently, reflecting different hemodynamic patterns and embryological origins. Thus, the expressions of PDIA1 and ENO1 will also be investigated in the endothelium of the inner curvature of the aorta, a region prone to inflammation/oxidative stress, in relation to the outer curvature, reflecting an abnormal pattern of shear forces. These results may contribute to elucidate mechanisms associated with aortic disease. (AU)