Investigation of peri/epicellular protein disulphide isomerase as a novel regulator of the platelet-endothelium interaction in normoglycaemia and Diabetes

• Grant number: 20/15944-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2021
• End date: May 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Renato Simões Gaspar
• 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

Abstract

Diabetes is a chronic and epidemic disease with high socio-economical cost worldwide, being characterized by increased risk of cardiovascular disease (CVD) and thromboembolic event. Upon endothelial dysfunction, platelets bind to endothelial cells to precipitate thrombus formation in a process that is not fully understood. Specifically, it is still unclear which surface proteins regulate platelet-endothelium interaction. In this regard, our lab has shown that peri/epicellular (pec) protein disulphide isomerase A1 (pecPDI) influences adhesion and migration of vascular cells. Therefore we hypothesize that pecPDI may regulate adhesion molecules on the surface of endothelial cells and platelets that influence the binding of these cells in physiological and pathological settings. Moreover, previous evidence suggests PDI is involved in Diabetes, therefore the impact of pecPDI will be assessed in diabetic mice in vivo and hyperglycaemic cells in vitro. Our main goal is to examine if pecPDI regulates platelet-endothelium interaction in normoglycaemia and Diabetes. Specifically, we will assess if pecPDI inhibition or genetic deletion of PDI affects expression levels of adhesion proteins, such as integrin beta 3, platelet and endothelial cell adhesion molecule 1 (PECAM-1), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), in hyperglycaemic endothelial cells in vitro; which adhesion molecules are targeted by pecPDI and how does pecPDI influence platelet-endothelium interaction in normo and Hyperglycaemia. Finally we will assess the importance of PDI to modulate platelet-endothelium interaction and thrombus formation in diabetic mice using intravital microscopy. Our lab is uniquely positioned to study how pecPDI associates with adhesion molecules, given the extensive techniques developed throughout decades of intensive scientific output. Altogether, the elucidation of novel molecules regulated by pecPDI, as well as mechanistic basis for platelet-endothelium interaction in normoglycaemia and Diabetes will expand the relevance of pecPDI to cell function and potentially lead to novel targets to treat and prevent thrombotic diseases in Diabetes. (AU)

Scientific publications

(4)

(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)

GASPAR, RENATO S.; MANSILLA, SANTIAGO; VIEIRA, VICTOR A.; SILVA, LUDMILA B. DA; GIBBINS, JONATHAN M.; CASTRO, LAURA; TROSTCHANSKY, ANDRES; PAES, ANTONIO MARCUS DE A.. The protein disulphide isomerase inhibitor CxxCpep modulates oxidative burst and mitochondrial function in platelets. Free Radical Biology and Medicine, v. 172, p. 668-674, AUG 20 2021. (20/15944-8)

GASPAR, RENATO SIMOES; ROSSI, LUDOVICO; HONE, THOMAS; DORNELLES, ANDRE ZUANAZZI. Income inequality and non-communicable disease mortality and morbidity in Brazil States: a longitudinal analysis 2002-2017. LANCET REGIONAL HEALTH-AMERICAS, v. 2, p. 9-pg., 2021-10-01. (20/15944-8)

GASPAR, RENATO SIMOES; REZENDE, LEANDRO F. M.; LAURINDO, FRANCISCO RAFAEL MARTINS. Analysing the impact of modifiable risk factors on cardiovascular disease mortality in Brazil. PLoS One, v. 17, n. 6, p. 15-pg., 2022-06-22. (20/15944-8, 13/07937-8)

GASPAR, RENATO SIMOES; LAURINDO, FRANCISCO RAFAEL MARTINS. Sulfenylation: an emerging element of the protein disulfide isomerase code for thrombosis. Journal of Thrombosis and Haemostasis, v. 21, n. 8, p. 4-pg., 2023-08-01. (20/15944-8, 13/07937-8)