Protein disulfide isomerase plasma levels in healthy humans reveal proteomic signatures involved in contrasting endothelial phenotypes

Author(s):Show less -

Santos de Oliveira, Percillia Victoria ^[1] ; Garcia-Rosa, Sheila ^{[2, 3]} ; Azevedo Sachetto, Ana Teresa ^[4] ; Soares Moretti, Ana Iochabel ^[1] ; Debbas, Victor ^[1] ; De Bessa, Tiphany Coralie ^[1] ; Silva, Nathalia Tenguan ^[1] ; Pereira, Alexandre da Costa ^[5] ; Martins-de-Souza, Daniel ^{[2, 3]} ; Santoro, Marcelo Larami ^[4] ; Martins Laurindo, Francisco Rafael ^[1]

Affiliation

^[1] Univ Sao Paulo, Hosp Clin HCFMUSP, LIM Biol Cardiovasc Translac 64, Inst Coracao InCor, Lab Biol Vasc, Fac Med, Av Eneas C Aguiar 44, Annex 2, 9th Floor, BR-05403904 Sao Paulo, SP - Brazil

^[2] Conselho Nacl Desenvolvimento Cient & Tecnol, Inst Nacl Biomarcadores Neuropsiquiatria INBION, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, Lab Neuroprote, Campinas, SP - Brazil

^[4] Inst Butantan, Lab Fisiopatol, BR-05503900 Sao Paulo - Brazil

^[5] Univ Sao Paulo, Med Sch Hosp, Heart Inst InCor, Lab Genet & Mol Cardiol, Sao Paulo - Brazil

• Document type: Journal article
• Source: REDOX BIOLOGY; v. 22, APR 2019.
• Web of Science Citations: 1

Abstract

Redox-related plasma proteins are candidate reporters of protein signatures associated with endothelial structure/function. Thiol-proteins from protein disulfide isomerase (PDI) family are unexplored in this context. Here, we investigate the occurrence and physiological significance of a circulating pool of PDI in healthy humans. We validated an assay for detecting PDI in plasma of healthy individuals. Our results indicate high inter-individual (median = 330 pg/mL) but low intra-individual variability over time and repeated measurements. Remarkably, plasma PDI levels could discriminate between distinct plasma proteome signatures, with PDI-rich ( > median) plasma differentially expressing proteins related to cell differentiation, protein processing, housekeeping functions and others, while PDI-poor plasma differentially displayed proteins associated with coagulation, inflammatory responses and immunoactivation. Platelet function was similar among individuals with PDI-rich vs. PDI-poor plasma. Remarkably, such protein signatures closely correlated with endothelial function and phenotype, since cultured endothelial cells incubated with PDI-poor or PDI-rich plasma recapitulated gene expression and secretome patterns in line with their corresponding plasma signatures. Furthermore, such signatures translated into functional responses, with PDI-poor plasma promoting impairment of endothelial adhesion to fibronectin and a disturbed pattern of wound-associated migration and recovery area. Patients with cardiovascular events had lower PDI levels vs. healthy individuals. This is the first study describing PDI levels as reporters of specific plasma proteome signatures directly promoting contrasting endothelial phenotypes and functional responses. (AU)

• FAPESP's process: 17/25588-1 - From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/07511-4 - Endoplasmic reticulum-plasma membrane contacts as hubs for NOx NADPH oxidase-dependent cellular redox signaling
• Grantee: Tiphany Coralie de Bessa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/19866-9 - A new PDI activity assay in human plasma
• Grantee: Nathalia Tenguan Silva
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 14/20595-1 - 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
• Grantee: Percíllia Victória Santos de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/08711-3 - Developing a predictive test for a successful medication response and understanding the molecular bases of schizophrenia through proteomics
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 13/25177-0 - Involvement of Von Willebrand factor in hemostatic disturbances induced by Bothrops jararaca snake venom: experimental study
• Grantee: Marcelo Larami Santoro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/10068-4 - Multi-User Equipment approved in grant 13/08711-3: mass spectrometer waters SYNAPT G2-Si HDMS + nanoACQUITY UPLC
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC