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Modulation of mitochondrial dynamics by isomerase-A1 dissulfide protein in vascular smooth muscle cell

Grant number: 19/04809-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2019
Effective date (End): March 31, 2020
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Francisco Rafael Martins Laurindo
Grantee:Rafael Felipe Gonçalves Rodrigues
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

Protein Isomerase Disulfide (PDI) is a reticulum chaperone involved in oxidation and reduction, it is a member of thioredoxin superfamily which catalyses the isomerization and formation of disulfide bounds, an essential component in the protein synthesis and processing. PDI have an important role in the cytoskeleton organization and migration of vascular muscular smooth muscle (VSMC). Recently, PDI was described as an extracellular form counterbalance of constrictive remodeling in VSMC. The VSMC phenotype is related to extrinsic and intrinsic cellular growth-factors, including NOX-dependent redox signaling. Our group showed recently effects of PDI overexpression in an inducible doxycycline VSMC model (VSMC_TetON) which increases of NADPH Oxidase 1 (NOX1) mRNA expression in the first 24 hours, with a late increase in 72 hours. After 72h these events coincide with the increase of differentiation cell markers as calponin and smoothelin, as well as increased cell length. These data suggest that overexpression of PDI induces the NOX activation, mainly NOX1, playing an important role in the VSMC phenotype. It is known that the cellular differentiation process demands a high level of energy and like the ATP synthesis and oxidant generation occurs inside the mitochondria, our hypothesis is that the PDI overexpression in VSMC may affect the mitochondrial architecture measure by structural dynamics and mass of this organelle. In addition, in VSMC knockdown in PDI, respiratory function impairment occurs, with mitochondrial and dysfunction in endothelial redox activity, with increased oxidation of the DRP1 protein. In addition, the normal expression of PDI leads to overexpression of DRP1, with less fragmentation mitochondrial. This pattern led us to the hypothesis that PDI-NOX may be related to a process of transformation of mitochondrial phenotype, mediated by DRP1 protein.