Integration between oxidative stress and inflammation mediated by myeloperoxidase in atherosclerosis vascular remodeling: role of protein disulfide isomerase and neutrophil nets

• Grant number: 12/00014-9
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: February 01, 2012
• End date: May 31, 2012
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Haniel Alves Araujo
• Supervisor: Peter Libby
• 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: Harvard University, Boston, United States
• Associated to the scholarship: 10/06360-0 - Study of gene expression in the vascular repair response after injury : effects of protein disulfide isomerase suppression, BP.IC

Abstract

Vascular remodeling has wide significance as a prototype of common events responsible for physiological adaptations or pathological changes in vascular disease. The progression and destabilization of atherosclerotic plaque and associated vascular remodeling integrate complex signaling mechanisms, including chronic inflammation and oxidative stress. Thus, the hypothesis of this study is that the myeloperoxidase exerces a fundamental role in this process, acting through the formation of neutrophil NETs, contributing to the exacerbation of chronic inflammation and redox balance. Moreover, we postulate that chaperones (with emphasis on protein disulfide isomerase - PDI) present in these NETs may interact in the organization of the response, correlating these processes and the endoplasmic reticulum stress. The objective of this project is the study of myeloperoxidase during the formation of NETs in vivo models of analysis of progression and stability of atherosclerotic plaque, investigating the interactions with oxidative stress - NADPH oxidase - and convergence with the ER stress-mediated chaperones. The specific goals are: 1 - to investigate the interaction between oxidative stress and inflammation in neutrophils during the formation of NETs mediated by myeloperoxidase. 2 - Determine the mechanisms by which myeloperoxidase may influence the instability and rupture of atherosclerotic plaque and vascular remodeling. 3 - To investigate the interaction between chaperones (PDI) and myeloperoxidase NETs linking ER stress, redox imbalance and chronic inflammation in vascular remodeling and plaque destabilization. (AU)