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Characterisation of Proendothelin-1 Derived Peptides and Evaluation of Their Utility As Biomarkers of Vascular and Renal Pathologies

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Characterisation of Proendothelin-1 Derived Peptides and Evaluation of Their Utility As Biomarkers of Vascular and Renal Pathologies Characterisation of Proendothelin-1 Derived Peptides and Evaluation of Their Utility as Biomarkers of Vascular and Renal Pathologies Jale Yuzugulen A thesis submitted for the degree of Doctor of Philosophy (Ph.D) in the Barts and the London School of Medicine and Dentistry of the Queen Mary, University of London 2014 Centre for Translational Medicine & Therapeutics, William Harvey Research Institute, John Vane Science Centre Charterhouse Square London UK i Statement of originality I, Jale Yuzugulen, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: [ ] Date: 10/03/2014 ii List of publications and abstracts arising from this thesis: 1. Yuzugulen J, Wood EG, Douthwaite JA, Villar IC, Patel NS, Jegard J, Montoya A, Cutillas P, Hartley O, Ahluwalia A, Corder R. (2012) Characterization of Proendothelin-1 Derived Peptides Identifies a Co-secreted Modulator of ET-1 Vasoconstriction, and Provides Insights for Biomarker Measurements. Circulation. 126: A18898 (Poster presentation; AHA meeting; Core 7: Vascular Disease: Biology and Clinical Science). 2. Dhaun N, Yuzugulen J, Kimmitt RA, Wood EG, Lilitkarntakul P, MacIntyre IM, Goddard J, Webb DJ, Corder R. Plasma proendothelin-1 peptide concentrations rise in CKD and following selective endothelin-A receptor antagonism. Manuscript in preparation. 3. Yuzugulen J, Wood EG, Villar IC, Douthwaite JA, Patel NSA, Jegard J, Montoya A, Cutillas P, Gaertner H, Rossitto-Borlat I, Rose K, Hartley O, Ahluwalia A, Corder R. (2013). Characterisation Of the “Endothelin-Like Domain Peptide” (ELDP) Co-synthesised With Endothelin-1 from the EDN1 gene. Life Sciences: Vol 93 Issues 25-26, 18 Dec 2013, page e2 [Oral presentation; Special Section of Thirteenth International Conference on Endothelin (ET-13), Tokyo, September 8- 11, 2013]. 4. Yuzugulen J, Kimmitt R, Dhaun N, Wood EG, Goddard J, Webb DJ, Corder R. (2013). Effect of sitaxentanon plasma biomarkers of proendothelin-1 synthesis in patients with chronic kidney disease. Life Sciences: Vol 93 Issues 25-26, 18 Dec 2013, page e66 [Poster presentation; Special Section of Thirteenth International Conference on Endothelin (ET-13), Tokyo, September 8-11, 2013]. 5. Yuzugulen J, Lilitkarntakul P, Wood EG, Kimmitt RA, Dhaun N, Goddard J, Webb DJ, Corder R. (2013). Evaluation Of Urinary and Plasma Endothelin-Like Domain Peptide (ELDP) in Chronic Kidney Disease. Life Sciences: Vol 93 Issues 25-26, 18 Dec 2013, page e14 [Poster presentation; Special Section of Thirteenth International Conference on Endothelin (ET-13), Tokyo, September 8-11, 2013]. 6. Yuzugulen J, Villar IC, Wood EG, Douthwaite JA, Patel NSA, Jegard J, Montoya A, Cutillas P, Gaertner H, Rossitto-Borlat I, Rose K, Hartley O, Ahluwalia A, Corder R. (2012). The Endothelin-Like Domain Peptide (ELDP) co-synthesised with endothelin-1 from the EDN1 gene modulates ET-1 induced vasoconstriction and has potential for biomarker measurements. Proceedings of the British iii Pharmacological Society at http://www.pA2online.org/abstracts/Vol10Issue4abst186P.pdf. [Poster presentation, BPS Winter Meeting. London]. iv Abstract Endothelin-1 (ET-1), the potent vasoconstrictor peptide, is synthesised from the 212 amino acid precursor preproendothelin-1 (ppET-1). ET-1 is strongly implicated in cardiac and renal pathologies. However, ET receptor antagonists demonstrated only limited efficacy in clinical trials of chronic heart failure (HF) and hypertension. ET-1 has a short circulating half-life and its plasma measurements have been inaccurate. Thus, alternative ppET-1 derived peptides may be more stable and could serve as better biomarkers of ET-1 synthesis. Moreover, alternative ppET-1 derived peptides may contribute to the biological effects resulting from EDN1 gene expression and may be interacting with the vasoconstrictor responses of ET-1 or other mediators. The aims of these investigations were to characterise ppET-1 derived peptide products and to evaluate their potential as biomarkers of ET-1 synthesis. A combination of specific immunoassays and HPLC were used to characterise ppET-1 processing in human endothelial (EA.hy 926) and epithelial (A549) cells in culture. NT- proET-1 (ppET-1[18 – 50]), endothelin-like domain peptide (ELDP, ppET-1[93 – 166]) and CT-proET-1 (ppET-1[169 – 212]) were identified in conditioned media samples as the main ppET-1 derived peptide products. The identities of ELDP and CT-proET-1 were confirmed by LC-MS/MS mass spectrometry. The three ppET-1 peptides were chemically synthesised and their in vivo clearance was investigated in male Wistar rats. Arterial plasma levels after intravenous administration of proET-1 peptides showed rapid clearance (<5 min) of NT-proET-1, while CT-proET- 1 had the slowest clearance rate. Studies of proET-1 peptide stability in blood samples also showed NT-proET-1 had lower stability. Specific double-recognition site sandwich ELISAs optimised for plasma measurements were used to evaluate plasma concentrations of ELDP and CT-proET-1 in patients with chronic HF and chronic kidney disease (CKD). In conclusion, the results described in this thesis provide further evidence linking ET-1 to cardiac and renal disease processes. But the small differences between healthy individuals and patients with cardiovascular or renal disease indicate only a limited potential for proET-1 peptides as diagnostic biomarkers of EDN1-linked pathologies. v Table of Contents Statement of originality ii List of publications and abstracts arising from this thesis iii Abstract v Table of contents vi List of Figures xiv List of Tables xvi Abbreviations xviii Acknowledgements xxiiv Chapter 1 –Introduction 1 1.1 Identification of endothelin-1 2 1.2 Processing of proendothelin-1 4 1.3 The role of pro-hormone/pro-protein convertases (PCs) 7 1.4 Endothelin Converting Enzyme (ECE) 8 1.4.1 Structural features of ECE-1 9 1.4.2 Analysing the physiological role of ECE-1 in ET-1 biosynthesis 12 1.4.2.1 Inhibitor studies with protease inhibitors 12 1.4.2.2 Inhibitor studies in endothelial cells 13 1.4.2.3 Functional studies 14 1.5 Alternative processing pathways of ET-1 synthesis 15 1.5.1 Matrix metalloproteinase-2 15 1.5.2 Chymase 15 1.6 Factors regulating ET-1 biosynthesis in endothelial cells 16 1.6.1 Fluid shear stress 17 1.6.2 Krüppel-like factor 2 (KLF2) 18 1.6.3 Calcium (Ca2+) ionophores 18 1.6.4 Thrombin 19 1.6.5 Bacterial lipopolysaccharide (LPS) 19 vi 1.6.6 Insulin 20 1.7 Regulation of ET-1 synthesis in other cell types: 21 1.7.1 Vascular smooth muscle cells 21 1.7.2 Pulmonary arterial smooth muscle cells (PASMC) 22 1.7.3 Cardiomyocytes 23 1.7.4 Airway epithelial cells 23 1.7.5 Cancer cells 24 1.8 Endothelin receptors 25 1.8.1 ET receptor antagonists and clinical trials 27 1.9 Evolutionary perspective of ET-1 and ET receptors 31 1.10 Vascular actions of ET-1 35 1.10.1 Signal transduction and downstream effectors 35 1.10.2 Mitogenic actions 37 1.10.3 Inflammatory effects 37 1.10.4 Endothelial function 38 1.11 The role of ET-1 in the pathophysiology of cardiovascular disease 39 1.11.1 Atherosclerosis 39 1.11.2 Hypertension 40 1.11.3 Chronic heart failure 40 1.12 The area of unmet clinical need and requirement of biomarkers 41 1.12.1 Endothelial dysfunction 41 1.12.2 Changes in vascular function with age, predictive of cardiovascular disease risk 43 1.12.3 Current methodologies measuring endothelial function 44 1.13 Proposed Biomarker(s) 47 1.13.1 ET-1 as a biomarker of cardiovascular disease risk 47 1.13.2 Plasma measurements of big ET-1 and C-Terminal fragment 48 1.13.3 ProET-1 derived peptides as alternative markers of ET-1 synthesis 48 1.13.4 Other biomarkers of vascular function and risk 49 1.14 Hypothesis and aims of this thesis 58 vii Chapter 2 – Materials and methods 60 2.1 MATERIALS 61 2.1.1 Reagents and Solutions 61 2.1.2 Equipment 65 2.1.3 Preproendothelin-1 peptides 65 2.1.3.1 Direct infusion of proET-1 peptides on Orbitrap 66 2.1.4 Preproendothelin-1 antibodies 67 2.2 METHODS 69 2.2.1 Cell culture 69 2.2.2 Chemiluminescence immunoassays 69 2.2.2.1 Assay buffers 69 2.2.2.2 Immunoassays for ET-1 and big ET-1 70 2.2.2.3 Immunoassays of NT-proET-1, ELDP and CT-proET-1 71 2.2.2.4 Immunoassay of ELDP and CT-proET-1 for plasma and urine measurements 71 2.2.3 Magnetic bead-based multiplex assays for proET-1 peptides 72 2.2.4 Production of new capture and detection antibodies for CT-proET-1 immunoassay 73 2.2.4.1 Reagents and solutions 74 2.2.4.1.1 Custom synthesised CT-proET-1 peptides 74 2.2.4.1.2 Conjugation buffers 74 2.2.4.1.3 Biotinylation of CT-proET-1 peptides and purified IgG 75 2.2.4.2 Coupling of synthetic N-terminal peptide of CT-proET-1 to an immunogenic carrier protein 77
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