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Regulation of redox homeostasis and integrated stress response by Protein Disulfide Isomerase (PDI): mechanisms and role in the pathophysiology and therapy of vascular diseases

Grant number: 09/54764-6
Support type:Research Projects - Thematic Grants
Duration: June 01, 2010 - May 31, 2016
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Francisco Rafael Martins Laurindo
Grantee:Francisco Rafael Martins Laurindo
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
Co-Principal Investigators:Lucia Rossetti Lopes

Abstract

Redox homeostasis depends on the regulated production of reactive oxygen species (ROS) via enzymatic sources such as the Nox family NADPH oxidase complex, the main source of ROs in vascular cells. Recent studies from our laboratory disclosed an important role of PDI in the regulation of NADPH oxidase. The important functional effects of PDI in NADPH oxidase in a number of distinct cell types, the physical proximity between POI and NADPH oxidase complex subunits and the important functional versatility of PDI regarding its interaction with other proteins, chaperone effect, redox control of membrane proteins and protein traffic strongly indicate that the study of mechanisms whereby PDI affects NADPH oxidase is likely to provide important information with respect to the regulation of cellular redox homeostasis by NADPH oxidase. The main objective of this Theme Project is to investigate such mechanisms in depth. In parallel, considering that PDI is an endoplasmic reticulum (ER) enzyme, we worked over our last Theme Project on the hypothesis that PDI has a role in the convergence between oxidative stress and ER stress and we collected data suggestive of such an important stress convergence in cellular models. It is possible that the effects of PDI on cellular redox homeostasis in vascular diseases strongly merge with the occurrence of ER stress. Therefore, a second goal of our Project is to further our understanding of redox PDI effects in the context of the convergence between NADPH oxidase and integrative cell response to ER stress. Specific goals of our project are: 1) to develop peptide and molecular tools to promote loss- or gain-of-function of PDI; 2) to investigate some post-translational modifications of PDI; 3) to evaluate the role of PDI in cell migration and associated redox and non-redox mechanisms; 4) to study the effect of PDI in the regulation of NO-superoxide interaction during laminar shear stress; 5) to investigate the role of lipd droplets as integrative platforms of redox processes dependent on PDI and NADPH oxidase; 6) to investigate mechanisms whereby redox processes, NADPH oxidase and PDI affect the adaptation to sustained ER stress in cell models; 7) to investigate, during vascular repair following angioplasty-induced injury, the effects of PDI modulation in redox homeostasis and ER stress signaling, as well as neointima extension and endothelial thrombogenicity; 8) to investigate a possible effect of PDI, redox processes and ER stress in the vascular phenotype associated with Marfan' s Syndrome. These results may indicate entirely novel pathways that can lead to therapeutic interventions for the control of redox homeostasis in vascular diseases. (AU)

Scientific publications (20)
(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)
DE BESSA, TIPHANY CORALIE; PAGANO, ALESSANDRA; SOARES MORETTI, ANA IOCHABEL; SANTOS OLIVEIRA, PERCILLIA VICTORIA; MENDONCA, SAMIR ANDRADE; KOVACIC, HERVE; MARTINS LAURINDO, FRANCISCO RAFAEL. Subverted regulation of Nox1 NADPH oxidase-dependent oxidant generation by protein disulfide isomerase A1 in colon carcinoma cells with overactivated KRas. CELL DEATH & DISEASE, v. 10, FEB 13 2019. Web of Science Citations: 1.
GIMENEZ, MARCELA; VERISSIMO-FILHO, SIDNEY; WITTIG, ILKA; SCHICKLING, BRANDON M.; HAHNER, FABIAN; SCHUERMANN, CHRISTOPH; NETTO, LUIS E. S.; ROSA, JOSE CESAR; BRANDES, RALF P.; SARTORETTO, SIMONE; CAMARGO, LIVIA DE LUCCA; ABDULKADER, FERNANDO; MILLER, JR., FRANCIS J.; LOPES, LUCIA ROSSETTI. Redox Activation of Nox1 (NADPH Oxidase 1) Involves an Intermolecular Disulfide Bond Between Protein Disulfide Isomerase and p47(phox) in Vascular Smooth Muscle Cells. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, v. 39, n. 2, p. 224-236, FEB 2019. Web of Science Citations: 0.
GUIDO, MARIA C.; DEBBAS, VICTOR; SALEMI, VERA M.; TAVARES, ELAINE R.; MEIRELLES, THAYNA; ARAUJO, THAIS L. S.; NOLASCO, PATRICIA; FERREIRA-FILHO, JULIO C. A.; TAKIMURA, CELSO K.; PEREIRA, LYGIA V.; LAURINDO, FRANCISCO R. Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2018. Web of Science Citations: 0.
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.; JO, HANJOONG; TRAN, NGOC-VINH; EBERSBERGER, INGO; BRANDES, RALF P.; BONATTO, DIEGO; LAURINDO, FRANCISCO R. M. Conserved Gene Microsynteny Unveils Functional Interaction Between Protein Disulfide Isomerase and Rho Guanine-Dissociation Inhibitor Families. SCIENTIFIC REPORTS, v. 7, DEC 8 2017. Web of Science Citations: 5.
TANAKA, LEONARDO Y.; LAURINDO, FRANCISCO R. M. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation. Free Radical Biology and Medicine, v. 109, n. SI, p. 11-21, AUG 2017. Web of Science Citations: 13.
TANAKA, LEONARDO Y.; LAURINDO, FRANCISCO R. M. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation. Free Radical Biology and Medicine, v. 109, n. SI, p. 11-21, AUG 2017. Web of Science Citations: 0.
SOARES MORETTI, ANA IOCHABEL; MARTINS LAURINDO, FRANCISCO RAFAEL. Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum. Archives of Biochemistry and Biophysics, v. 617, n. SI, p. 106-119, MAR 1 2017. Web of Science Citations: 29.
TREVELIN, SILVIA C.; CARLOS, DANIELA; BERETTA, MATTEO; DA SILVA, JOAO S.; CUNHA, FERNANDO Q. Diabetes Mellitus and Sepsis: A Challenging Association. Shock, v. 47, n. 3, p. 276-287, MAR 2017. Web of Science Citations: 12.
ARAUJO, THAIS L. S.; ZEIDLERA, JULIANNA D.; OLIVEIRA, PERCILLIA V. S.; DIAS, MATHEUS H.; ARMELIN, HUGO A.; LAURINDO, FRANCISCO R. M. Protein disulfide isomerase externalization in endothelial cells follows classical and unconventional routes. Free Radical Biology and Medicine, v. 103, p. 199-208, FEB 2017. Web of Science Citations: 11.
TREVELIN, SILVIA CELLONE; DOS SANTOS, CELIO XAVIER; FERREIRA, RAPHAEL GOMES; LIMA, LARISSA DE SA; SILVA, RANGEL LEAL; SCAVONE, CRISTOFORO; CURI, RUI; CARLOS ALVES-FILHO, JOSE; CUNHA, THIAGO MATTAR; ROXO-JUNIOR, PERSIO; CERVI, MARIA-CELIA; MARTINS LAURINDO, FRANCISCO RAFAEL; HOTHERSALL, JOHN STEPHEN; COBB, ANDREW M.; ZHANG, MIN; IVETIC, ALEKSANDAR; SHAH, AJAY M.; LOPES, LUCIA ROSSETTI; CUNHA, FERNANDO QUEIROZ. Apocynin and Nox2 regulate NF-kappa B by modifying thioredoxin-1 redox-state. SCIENTIFIC REPORTS, v. 6, OCT 4 2016. Web of Science Citations: 14.
TANAKA, LEONARDO Y.; ARAUJO, HANIEL A.; HIRONAKA, GUSTAVO K.; ARAUJO, THAIS L. S.; TAKIMURA, CELSO K.; RODRIGUEZ, ANDRES I.; CASAGRANDE, ANNELISE S.; GUTIERREZ, PAULO S.; LEMOS-NETO, PEDRO ALVES; LAURINDO, FRANCISCO R. M. Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect. Hypertension, v. 67, n. 3, p. 613-622, MAR 2016. Web of Science Citations: 14.
GIMENEZ, MARCELA; SCHICKLING, BRANDON M.; LOPES, LUCIA R.; MILLER, JR., FRANCIS J. Nox1 in cardiovascular diseases: regulation and pathophysiology. Clinical Science, v. 130, n. 3, p. 151-165, FEB 1 2016. Web of Science Citations: 17.
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.
DEMASI, MARILENE; SIMOES, VANESSA; BONATTO, DIEGO. Cross-talk between redox regulation and the ubiquitin-proteasome system in mammalian cell differentiation. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1850, n. 8, SI, p. 1594-1606, AUG 2015. Web of Science Citations: 7.
TREVELIN, SILVIA CELLONE; LOPES, LUCIA ROSSETTI. Protein Disulfide Isomerase and Nox: New Partners in Redox Signaling. CURRENT PHARMACEUTICAL DESIGN, v. 21, n. 41, p. 5951-5963, 2015. Web of Science Citations: 18.
LAURINDO, FRANCISCO R. M.; ARAUJO, THAIS L. S.; ABRAHAO, THALITA B. Nox NADPH Oxidases and the Endoplasmic Reticulum. Antioxidants & Redox Signaling, v. 20, n. 17, p. 2755-2775, JUN 10 2014. Web of Science Citations: 68.
BASSI, E.; LIBERMAN, M.; MARTINATTI, M. K.; BORTOLOTTO, L. A.; LAURINDO, F. R. M. Lipoic acid, but not tempol, preserves vascular compliance and decreases medial calcification in a model of elastocalcinosis. Brazilian Journal of Medical and Biological Research, v. 47, n. 2, p. 119-127, Fev. 2014. Web of Science Citations: 3.
WATANABE, MONICA M.; LAURINDO, FRANCISCO R. M.; FERNANDES, DENISE C. Methods of measuring protein disulfide isomerase activity: a critical overview. FRONTIERS IN CHEMISTRY, v. 2, 2014. Web of Science Citations: 15.
AMANSO, ANGELICA M.; DEBBAS, VICTOR; LAURINDO, FRANCISCO R. M. Proteasome Inhibition Represses Unfolded Protein Response and Nox4, Sensitizing Vascular Cells to Endoplasmic Reticulum Stress-Induced Death. PLoS One, v. 6, n. 1 JAN 26 2011. Web of Science Citations: 26.

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