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      Circulating Protein Biomarkers in Systemic Sclerosis Related Pulmonary Arterial Hypertension: A Review of Published Data

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          Abstract

          Pulmonary arterial hypertension (PAH) develops in 7–12% of patients with systemic sclerosis (SSc) and is associated with a 3 year survival of 52%. Early detection by screening is therefore recommended for all patients with SSc. Historically, screening has been performed using echocardiography and measurement of gas transfer. More recently the DETECT protocol, using a combination of biomarkers (including N-terminal pro-brain natriuretic peptide) and clinical parameters, has been developed. The optimal method of screening for PAH with high sensitivity and specificity is, however, not clear. Protein expression differences between different SSc disease phenotypes have been reported, and include alterations in concentration of NT-proBNP, endoglin, soluble vascular endothelial growth factor receptor 1, placenta growth factor, growth differentiation factor-15, vascular endothelial growth factor alpha, resistin-like molecule beta, and soluble thrombomodulin. This review summarizes the current knowledge of these protein changes in patients with SSc and PAH.

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          Most cited references 32

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          Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies.

          The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been shown to play major roles not only in physiological but also in most pathological angiogenesis, such as cancer. VEGF belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure. VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1 in mice). On the other hand, VEGF-C/VEGF-D and their receptor, VEGFR-3 (Flt-4), mainly regulate lymphangiogenesis. The VEGF family includes other interesting variants, one of which is the virally encoded VEGF-E and another is specifically expressed in the venom of the habu snake (Trimeresurus flavoviridis). VEGFRs are distantly related to the PDGFR family; however, they are unique with respect to their structure and signaling system. Unlike members of the PDGFR family that strongly stimulate the PI3K-Akt pathway toward cell proliferation, VEGFR-2, the major signal transducer for angiogenesis, preferentially utilizes the PLCγ-PKC-MAPK pathway for signaling. The VEGF-VEGFR system is an important target for anti-angiogenic therapy in cancer and is also an attractive system for pro-angiogenic therapy in the treatment of neuronal degeneration and ischemic diseases.
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            Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.

            Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension (PPH). Plasma BNP was measured in 60 patients with PPH at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (>/=150 pg/mL) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (P /=180 pg/mL) than for those with an inframedian value (P<0.0001). A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PPH.
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              Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR.

               J Winer,  J. Park,  N Ferrara (1994)
              The recently identified placenta growth factor (PIGF) is a member of the vascular endothelial growth factor (VEGF) family of growth factors. PIGF displays a 53% identity with the platelet-derived growth factor-like region of VEGF. By alternative splicing of RNA, two PIGF isoforms are generated: PIGF131 (PIGF-1) and PIGF152 (PIGF-2). Relative to PIGF131, PIGF152 has a 21-amino acid insertion enriched in basic amino acids. Little is known at the present time about the significance and function of these proteins. To assess their potential role, we cloned the cDNAs coding for both isoforms, expressed them in mammalian cells, and purified to apparent homogeneity the recombinant proteins. Like VEGF, the PIGF isoforms are homodimeric glycoproteins. PIGF131 is a non-heparin binding protein, whereas PIGF152 strongly binds to heparin. We examined the ability of PIGF to bind to soluble VEGF receptors, Flt-1 and Flk-1/KDR, and characterized the binding of PIGF to endothelial cells. While the PIGF proteins bound with high affinity to Flt-1, they failed to bind to Flk-1/KDR. Binding of 125I-PIGF to human endothelial cells revealed two classes of sites, having high and low affinity. The high affinity site is consistent with Flt-1; the identity of the low affinity site remains to be determined. Purified PIGF isoforms had little or no direct mitogenic or permeability-enhancing activity. However, they were able to significantly potentiate the action of low concentrations of VEGF in vitro and, more strikingly, in vivo.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                06 June 2018
                2018
                : 5
                Affiliations
                1Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield , Sheffield, United Kingdom
                2Pulmonary Vascular Diseases Unit, Royal Hallamshire Hospital , Sheffield, United Kingdom
                Author notes

                Edited by: Anne Hilgendorff, Ludwig-Maximilians-Universität München, Germany

                Reviewed by: Peter Korsten, Universitätsmedizin Göttingen, Germany; Eleni Papakonstantinou, Aristotle University of Thessaloniki, Greece

                *Correspondence: Robin Condliffe robin.condliffe@ 123456sth.nhs.uk

                This article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2018.00175
                5997816
                Copyright © 2018 Hickey, Lawrie and Condliffe.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 47, Pages: 7, Words: 5643
                Funding
                Funded by: University of Sheffield 10.13039/501100000858
                Categories
                Medicine
                Mini Review

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