Role of protein disulfide isomerase (PDI) in the EGFR activation and regulation of the expression/activity of the NADPH oxidase in vascular smooth muscle cells

• Grant number: 14/09334-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2014
• End date: August 06, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Lucia Rossetti Lopes
• Grantee: Simone Marcieli Sartoretto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID
• Associated scholarship(s): 16/07004-0 - Role of protein disulfide isomerase in the regulation of Nox1 activation and EGFR signaling in cancer, BE.EP.PD

Abstract

The oxidoreductase found in the endoplasmic reticulum, protein disulfide isomerase (PDI), has recently gained notoriety in cell signaling. Studies from our group have shown that PDI is involved in the regulation of NADPH oxidase enzymatic complex, which is the main source of reactive oxygen species (ROS) in the cardiovascular system. Our group has recently demonstrated that PDI overexpression in vascular smooth muscle cells (VSMC) increases Nox1 expression/activation and cell migration. These studies indicate an association between PDI and Nox1 expression/activity in VSMC. Other studies demonstrated that VSMC migration is dependent of EGFR transactivation, ROS generation by Nox1, and matrix metalloproteinases activation. Additionally, these authors also demonstrated that oxidative stress promotes EGFR activation by increasing release of EGFR ligands in the extracellular medium. Nonetheless, the role of PDI on EGFR activation and Nox1-depedent VSMC migration remains elusive. Identify the mechanisms accountable for EGFR activation is imperative due the importance of this receptor on vascular diseases such as hypertension. Results obtained in our laboratory show that arteries from spontaneously hypertensive rats have an increase in PDI and Nox 1 expression and activity. Therefore, the goal of this project is to investigate the role of PDI on EGFR activation and Nox 1-dependent CMVL migration. (AU)