Protein Disulfide Isomerase (PDI) as a marker of risk for thrombosis and/or accelerated progression of atherosclerosis in patients with familial hipercholesterolemia and in experimental model

• Grant number: 14/20595-1
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): January 01, 2015
• Effective date (End): June 30, 2019
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Percíllia Victória Santos de Oliveira
• Home 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

The Protein Disulfide Isomerase (PDI) is a chaperone-dithiol-disulfide oxidoreductase from the thioredoxin superfamily, which catalyzes the disulfide bonds formation and isomerization as an essential functional component of proteins synthesis and processing. Although it is mainly located in the endoplasmic reticulum, PDI has been reported in other intracellular locations as well as on the cell surface. The PDI is secreted by several cell types and was also found in microparticles. Particularly in platelets and endothelial cells, PDI and other relevant thiol isomerases exert functional effects, it is also important in thrombus formation after vascular injury. Dyslipidemia, particularly increased level of LDL in the blood plasma, occupies a more important role in the development of atherosclerosis. Thus, hypercholesterolemia is an established risk factor for atherogenesis and depends on environmental and genetic factors. Atherosclerosis is a chronic and progressive inflammatory disease characterized by lipids and fibrous elements accumulation in the arteries that hinders the blood flow even causing its obstruction. There are not still plasma markers that indicates a greater risk of unstable lesions and accelerated progression of atherosclerosis. Recent studies in our laboratory have addressed the expression of PDI in human atherosclerotic plaques and found a strong expression of PDI, and a significant correlation between the direct PDI immunostaining and expansive vessel remodeling as well as the complexity of the plate (strongly expressed in arterial thrombus). It has also been shown that injured arteries of rabbits secrete PDI ex vivo and the thrombus formed after injury shows expression of PDI on its surface. Therefore, it is possible to propose that PDI and, in general, thiol isomerases, are an important marker of lesion instability and risk of thrombosis. Furthermore, we propose that the circulating plasma PDI, which should reflect the total pool of extracellular PDI could be a marker of risk for accelerated progression and instability of plaque and subsequent thrombosis. Therefore, the aim of this study is to investigate whether the current PDI is an independent risk marker for thrombosis, endothelial dysfunction and/or inflammation in atherosclerotic disease in patients with familial hypercholesterolemia and in experimental models. (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)

SANTOS DE OLIVEIRA, PERCILLIA VICTORIA; GARCIA-ROSA, SHEILA; AZEVEDO SACHETTO, ANA TERESA; SOARES MORETTI, ANA IOCHABEL; DEBBAS, VICTOR; DE BESSA, TIPHANY CORALIE; SILVA, NATHALIA TENGUAN; PEREIRA, ALEXANDRE DA COSTA; MARTINS-DE-SOUZA, DANIEL; SANTORO, MARCELO LARAMI; MARTINS LAURINDO, FRANCISCO RAFAEL. Protein disulfide isomerase plasma levels in healthy humans reveal proteomic signatures involved in contrasting endothelial phenotypes. REDOX BIOLOGY, v. 22, APR 2019. Web of Science Citations: 0.

DE BESSA, TIPHANY CORALIE; PAGANO, ALESSANDRA; SOARES MORETTI, ANA IOCHABEL; SANTOS OLIVEIRA, PERCILLIA VICTORIA; MENDONCA, SAMIR ANDRADE; KOVACIC, HERVE; MARTINS LAURINDO, FRANCISCO RAFAEL. Subverted regulation of Nox1 NADPH oxidase-dependent oxidant generation by protein disulfide isomerase A1 in colon carcinoma cells with overactivated KRas. CELL DEATH & DISEASE, v. 10, FEB 13 2019. Web of Science Citations: 0.

OLIVEIRA, PERCILLIA V. S.; LAURINDO, FRANCISCO R. M. Implications of plasma thiol redox in disease. Clinical Science, v. 132, n. 12, p. 1257-1280, JUN 29 2018. Web of Science Citations: 6.

ARAUJO, THAIS L. S.; ZEIDLERA, JULIANNA D.; OLIVEIRA, PERCILLIA V. S.; DIAS, MATHEUS H.; ARMELIN, HUGO A.; LAURINDO, FRANCISCO R. M. Protein disulfide isomerase externalization in endothelial cells follows classical and unconventional routes. Free Radical Biology and Medicine, v. 103, p. 199-208, FEB 2017. Web of Science Citations: 11.