Role of protein disulfide isomerase in the redox regulation of ADAM17 activation and EGFR signaling in vascular disease

• Grant number: 13/18300-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 20, 2014
• End date: January 19, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Lucia Rossetti Lopes
• Grantee: Marcela Gimenez
• Supervisor: Francis J. Miller Jr.
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Iowa, United States

Abstract

Oxidative stress in cardiovascular system can lead to diseases including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and restenosis. The primary source of reactive oxygen species (ROS) in vascular cells is NADPH oxidases (Nox) that are a family of seven membrane-integrated catalytic subunits, and regulatory subunits, according with cell type and stimuli. Among these isoforms, Nox1 have been implicated in vascular disorders such as hypertension and atherosclerosis. Dr. Francis Miller's research group from The University of Iowa has shown the role of Nox1 in the transactivation of EGFR and involvement of matrix metalloproteinases (MMPs) in biological processes such as migration and proliferation in vascular smooth muscle cells. We have shown that protein disulfide isomerase (PDI), a thioredoxin superfamily oxidoreductase from the endoplasmic reticulum can regulate the activity and expression of Nox1. Abundantly expressed, PDI displays interaction with redox and non redox proteins, which confers versatility to its cellular effects. In neutrophils, PDI redox dependently associates with p47phox and supports ROS generation. At the cell surface, PDI exerts thiol reductase and isomerase activities towards MMPs and a disintegrin and metalloproteinase family (ADAMs) both contain cysteine residues. These activities contribute to regulate ADAM17 shedding of cell surface EGF-like ligands. EGFR signaling has been shown to increase vascular smooth muscle cell migration and proliferation and these effects could contribute to neointimal hyperplasia after vascular injury. We hypothesize that changes in the redox environment or blockade of PDI thiols enhance ADAM17 activity and increase shedding of EGF ligands leading to EGFR signaling and Nox 1 expression. These cellular events cause activation of vascular smooth muscles and contribute to development of vascular disease. (AU)

Scientific publications

(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; 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. (13/18300-0, 13/03520-5, 13/07937-8, 09/54764-6)