Nox4 as an unfolded protein responsive (UPR)gene element-possible molecular pathway of endoplasmic reticulum stress convergence to oxidative stress in cardiovascualr system

• Grant number: 07/03102-8
• Support Opportunities: Scholarships abroad - New Frontiers
• Start date: January 15, 2008
• End date: January 14, 2009
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Celio Xavier da Costa dos Santos
• Grantee: Celio Xavier da Costa dos Santos
• Host Investigator: Ajay M. Shah
• Host 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
• Institution abroad: King's College London, England

Abstract

Unfolded or misfolded protein accumulation in the Endoplasmic reticulum (ER) induces an adaptative cellular response known as Unfolded Protein Response (URP) consisting of a cell signaling cascade which integrates ER to nuclear gene expression (Schröder & Kaufman, 2005). Sustained UPR leads to ER Stress condition which is implicated in cell death in many pathophysiological conditions including most cardiovascular disorders (Kaufman, 2002; Zhao & Ackerman, 2006; Marciniak & Ron D, 2006). ER Stress converges with Oxidative Stress during apoptosis eliciting Reactive Oxygen Species (ROS) production which has been attributed mainly to redox imbalances in the Endoplasmic Reticulum (Harding, 2003; Marciniak, 2004) and in less extent to mitochondria (Culliman & Diehl, 2006). Our recent work focuses in the convergence between ER stress and oxidative stress associated to vascular NADPH oxidase. We first described at protein level a spatial/physiological interdependency interdependence of NADPH oxidase components association to protein disulfide isomerase (PDI), an Endoplasmic Reticulum thiol oxireductase (Janiszewski et al., 2004). More recently we and others have shown that the NADPH oxidase isoform Nox 4 is up-regulated during ER Stress condition in parallel with increased Oxidative Stress (Santos et al, 2007; Pedruzzi et al., 2004). Several genes bearing a UPR-responsive element have been identified in cells during ER stress, including some indirectly associated with Oxidative Stress (Harding et al., 2002). However, the regulation Nox 4 gene expression in this condition is unknown. Thus, the main goal of this project is to clarify the regulation of Nox4 gene during ER Stress condition. (AU)