Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension

Department of Pediatric Critical Care, University of Colorado Denver, Denver, CO 80045, USA.
PROTEOMICS - CLINICAL APPLICATIONS (Impact Factor: 2.96). 06/2012; 6(5-6):257-67. DOI: 10.1002/prca.201100078
Source: PubMed


The prognosis for children with IPAH unresponsive to therapy is poor. We investigated the plasma proteome for a molecular basis of good versus poor outcome to long-term vasodilator therapy.
Plasma was collected at baseline or shortly after therapy initiation and following chronic vasodilator therapy, then divided into those with good outcome (n = 8), and those with a poor outcome (n = 7). To identify proteins unique to either outcome, we used differential gel electrophoresis and mass spectrometry. Results were confirmed by commercial enzyme-linked immunosorbent assay.
Before and after therapy, SAA-4 was 4-fold lower in those with good outcome compared to those with poor outcome, while serum paraoxonase/arylesterase-1 was increased 2-fold in those with good outcome versus poor outcome. After therapy, haptoglobin and hemopexin were 1.45- and 1.8-fold lower, respectively, in those with a good versus poor outcome. Among those with a good outcome, SAP was 1.3-fold lower prior to therapy.
SAP and SAA-4 regulate circulating mononuclear phagocytes. As such, they may contribute to the differential response to chronic vasodilator therapy in the context of inflammation in IPAH.

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Available from: David Dunbar Ivy, Oct 02, 2015
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    • "Second, this study supports the idea that iron plays a role in the development of PH, perhaps through increased iron-mediated protein carbonylation. Finally, we sought to investigate the plasma proteome of children with PH as a basis to predict outcome in response to vasodilator therapy[90]. Interestingly, we found correlations between serum amyloid A and serum amyloid P to outcome. "
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    ABSTRACT: Pulmonary hypertension (PH) is a fatal syndrome that arises from a multifactorial and complex background, is characterized by increased pulmonary vascular resistance and right heart afterload, and often leads to cor pulmonale. Over the past decades, remarkable progress has been made in reducing patient symptoms and delaying the progression of the disease. Unfortunately, PH remains a disease with no cure. The substantial heterogeneity of PH continues to be a major limitation to the development of newer and more efficacious therapies. New advances in our understanding of the biological pathways leading to such a complex pathogenesis will require the identification of the important proteins and protein networks that differ between a healthy lung (or right ventricle) and a remodeled lung in an individual with PH. In this article, we present the case for the increased use of proteomics-the study of proteins and protein networks- as a discovery tool for key proteins and protein networks operational in the PH lung. We review recent applications of proteomics in PH, and summarize the biological pathways identified. Finally, we attempt to presage what the future will bring with regard to proteomics in PH and offer our perspectives on the prospects of developing personalized proteomics and custom-tailored therapies.
    PROTEOMICS - CLINICAL APPLICATIONS 02/2015; 9(1-2). DOI:10.1002/prca.201400157 · 2.96 Impact Factor
    • "Sputum from adults and children with cystic fibrosis and from control subjects 2DE with MALDI-TOF and confirmed with nanoflow LC-MS (LCQ DECA ion trap) [41] Hellgren et al., 2008 Analyzed serum from children with idiopathic short stature for growth hormone-dependent nutrition markers Cationic exchange array (CM10) using SELDI-TOF-MS [42] Shi et al., 2009 Analyzed serum proteome for potential biomarkers of pediatric acute lymphoblastic leukemia SELDI-TOF-MS LC-MS/MS and validated using Protein Chip Immunoassays [43] Devarajan et al., 2010 Analyzed urine samples from children post cardiopulmonary bypass surgery for identification of early biomarkers of acute kidney injury after cardiac surgery in children SELDI-TOF MS [44] Cabras et al., 2010 Salivary secretory peptidome profile analyzed in children affected by type 1 diabetes High-resolution HPLC-ESI-MS/MS (LTQ Orbitrap XL) [45] Ignjatovic et al., 2011 Plasma proteome in children compared to adults 2D-DIGE [46] Egler et al., 2011 Identified circulating plasma biomarkers in high-risk neuroblastoma and their potential in relapse monitoring among pediatric patients SELDI-TOF-MS and Luminex Suspension Bead Array with Milliplex Human 39-Plex Cytokine [47] Rothwell et al., 2011 Compared plasma proteomic signature in 15 overweight adolescent girls with homeostasis model Assessment (HOMA) for insulin resistance Antibody array [48] Haskin et al., 2012 Insights on neoplastic stem cells from gel-based proteomics of childhood germ cell tumors 2DE, SDS-PAGE, and LC/MS/MS [49] Yeager et al., 2012 Investigated plasma proteomes for potential molecular markers that differentiate good versus poor response to long term vasodilator therapy in children with idiopathic pulmonary arterial hypertension 2DE with MS and validated with ELISA testing [50] Braoudakiet al., 2013 Plasma protein biomarkers in high-and low-risk pediatric acute lymphoblastic leukemia 2DE with MALDI-TOF-MS and validated by Western blotting. [51] Gitau et al., 2013 Differential proteome analysis of plasma and cerebrospinal proteomes from children with cerebral malaria and children with other encephalopathies 2DE with LC-MS/MS [52] Kentsis et al., 2013 Urine proteome analysis searching for improved diagnostic markers of Kawasaki disease Nanoflow HPLC system coupled to the hybrid linear ion trap-Fourier transform ion cyclotron resonance mass spectrometer [53] function analyzer have reported some functional differences comparing neonates and younger children to adults [25] [26]. "
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    ABSTRACT: Proteomics is a rapidly evolving ‘post-genomic’ science utilising advanced technologies in protein separation, identification, quantitation and heavily relying on bioinformatics. Proteomic research in paediatrics is important and most of the successes thus far are seen in research that utilise samples that require less invasive procedures and focus on prevailing childhood diseases such as acute lymphoblastic leukaemia and neuroblastoma. Recent advances in proteomics are helping to elucidate platelet processes that are relevant to bleeding and clotting disorders, as well as other important roles of platelets such as in angiogenesis and inflammation. Nevertheless, most of platelet proteome data obtained to date are derived from the adult population and the potential of platelet proteomic application in children has not yet been explored. As it happens in all research fields, there are additional challenges in studying children such as procuring sufficient biological samples and access to less common disease cohorts as compared to in adults. Furthermore, many of the prevalent platelet-mediated diseases in adults, such as coronary heart disease and atherosclerotic lesions, are believed to have origins during childhood. Hence, platelet proteomic research in children may reveal some important information on how platelet plays a role in the pathogenesis of disease. In this article, we refer to the current knowledge from platelet proteomic research strategies in adults and address the specific concerns in the study of paediatric samples.This article is protected by copyright. All rights reserved
    PROTEOMICS - CLINICAL APPLICATIONS 12/2014; 8(11-12). DOI:10.1002/prca.201400048 · 2.96 Impact Factor
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    • "Developmental programs driving lung vessels are thought to be perturbed in PAH, and decreased plasma vascular endothelial growth factor (VEGF) in infants with PAH may be a reflection of such disturbances (103). Recent proteomic studies have demonstrated clear feasibility in measuring plasma interleukins (ILs), acute phase proteins, and growth factors (104, 105). Some of these plasma proteins may simply reflect systemic inflammation (serum amyloid A), but may also be mechanistically linked to control of inflammatory cell phenotype (serum amyloid P). "
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    ABSTRACT: Therapeutic approaches in pediatric pulmonary arterial hypertension (PAH) are based primarily on clinician experience, in contrast to the evidence-based approach in adults with pulmonary hypertension. There is a clear and present need for non-invasive and objective biomarkers to guide the accurate diagnosis, treatment, and prognosis of this disease in children. The multifaceted spectrum of disease, clinical presentation, and association with other diseases makes this a formidable challenge. However, as more progress is being made in the understanding and management of adult PAH, the potential to apply this knowledge to children has never been greater. This review explores the state of the art with regard to non-invasive biomarkers in PAH, with an eye toward those adult PAH biomarkers potentially suitable for application in pediatric PAH.
    Frontiers in Pediatrics 02/2014; 2:7. DOI:10.3389/fped.2014.00007
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