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

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.

Vascular thiol isomerases in thrombosis: The yin and yang

“…Oliveira et al have recently shown that PDI plasma levels may discriminate apparently healthy individuals bearing distinct plasma proteome patterns, suggestive of cardiovascular and immunoinflammatory risk 73 . The median plasma levels were 330 pg/ml with high interindividual variability, but low intraindividual variability.…”

“…70 The prothrombin time and partial thromboplastin time coagulation assays were not prolonged. 73 The median plasma levels were 330 pg/ml with high interindividual variability, but low intraindividual variability.…”

GPx8 Expression in Rat Oocytes, Embryos, and Female Genital Organs During Preimplantation Period of Pregnancy

“…The true role of this protein here is unclear, but one can hypothesize that GPx8 could be involved in the maintenance of protein disulfide isomerase (PDI), which in ER acts in protein folding, since GPx8 and GPx7 may accept PDI as a reductant more efficiently than does GSH [ 11 ]. Moreover, a recently published study suggested that PDI is present in human plasma at important levels and could be even used as a marker for some medical conditions [ 29 ].…”

Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring

“…7 ). Among them, heat shock protein 90 kDa α (HSP90 α) is a potential factor driving the wound’s expected closure [ 24 ], while deficiency of protein disulfide isomerase (PDI), resulting in trauma-related migration and recovery area [ 25 ]. Tubulin alpha chain (TAC) may be involved in PLAB-mediated apoptosis of hypertrophic scar fibroblasts, and elongation factor 1-α 1 (EF-1α) potentially participate in scarless healing [ 26 , 27 ].…”