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Role of protein disulfide isomerase in NADPH oxidase dependent ROS generation during hypertension development

Grant number: 13/03520-5
Support type:Regular Research Grants
Duration: June 01, 2013 - May 31, 2015
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Lucia Rossetti Lopes
Grantee:Lucia Rossetti Lopes
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

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 PDI 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. Molecular processes underlying ROS-induced cardiovascular functional and structural alterations involve activation of redox sensitive signaling pathways . Superoxide anion and H2O2 stimulate mitogen activated protein kinases, tyrosine kinases and transcription factors and inactivate protein tyrosine phosphatases. ROS also increase intracellular calcium concentration and activate RhoA/Rho kinase leading to increased actin/myosin coupling and contraction. These effects occur through oxidative modification of proteins by altering key aminoacid residues such as cysteines in proteins. Although numerous studies have indicated that anti oxidants and ROS scavenging could prevent hypertension , extending this concept into the treatment of cardiovascular diseases has been problematic. In fact, several clinical trials have failed to show any benefits of antioxidant vitamins in prevention of cardiovascular disease. A highly likely reason is that ROS have important signaling properties and the non selective approach of scavenging all ROS could have deleterious effects. Another alternative to reduce oxidative stress is to interfere with the activity of the enzymes involved in ROS generation, particularly NADPH oxidase. We recently demonstrated that the redox endoplasmatic reticulum chaperone protein disulfide isomerase (PDI) modulates Ang II dependent dependent ROS generation in VSMCs. PDI associates with several isoforms of NADPH oxidase including Nox1, Nox2 and Nox4. Importantly an increase in Nox 1 expression has been associated to an increase in ROS generation in Ang II -induced hypertension. Furthermore, over expression of PDI increases. ROS generation and NADPH oxidase expression in rabbit aortic smooth muscle cells. However, the role of PDI in oxidative stress and vascular alterations observed in hypertension is unknown. The goal of the present study is to evaluate the effect of PDI in ROS generation during the development of hypertension. Our results could implicate PDI as a novel player in Ang II redox signaling and particularly in the oxidative stress and vascular dysfunction associated to hypertension. (AU)

Scientific publications (6)
(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)
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.
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.
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.
ANDROWIKI, ALINE C. D.; CAMARGO, LIVIA DE LUCCA; SARTORETTO, SIMONE; COUTO, GISELE K.; RIBEIRO, IZABELA M. R.; VERISSIMO-FILHO, SIDNEY; ROSSONI, LUCIANA V.; LOPES, LUCIA R. Protein disulfide isomerase expression increases in resistance arteries during hypertension development. Effects on Nox1 NADPH oxidase signaling. FRONTIERS IN CHEMISTRY, v. 3, MAR 27 2015. Web of Science Citations: 12.
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.
CAMARGO, LIVIA DE LUCCA; BABELOVA, ANDREA; MIETH, ANJA; WEIGERT, ANDREAS; MOOZ, JULIANE; RAJALINGAM, KRISHNARAJ; HEIDE, HEINRICH; WITTIG, ILKA; LOPES, LUCIA ROSSETTI; BRANDES, RALF P. Endo-PDI is required for TNF alpha-induced angiogenesis. Free Radical Biology and Medicine, v. 65, p. 1398-1407, DEC 2013. Web of Science Citations: 17.

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