Biomarkers are attractive non-invasive tools for estimating and monitoring pulmonary arterial hypertension (PAH) disease and for predicting survival in patients with PAH; therefore, many studies encouraged the investigation of new biomarkers to facilitate the diagnosis of PAH. Endostatin (ES) is an endogenous inhibitor of angiogenesis. It is produced by proteolytic cleavage of the collagen XVIII that is present in both normal and cancerous tissue. In vitro examination shows that ES can manage endothelial cells (EC) physiology in ways that could influence angiogenesis. For example, solvent ES hinders EC movement and prompts improvements of the cytoskeleton that incorporate the loss of Actin stretch strands and central grips. This effect embraces restrictions on the α5β1integrins, Tropomyosin, and putative heparan sulfate proteoglycans. Consequences for the human EC cytoskeleton include Es-induced down-regulation of Mitogen-actuated Protein Kinase (MAPK), Focal Adhesion Kinase (FAK), the Urokinase Plasminogen Activator (uPA) System, and the RhoA GTPase. Human ES has likewise been shown in a few investigations to repress EC multiplication. Moreover, ES-instigated cell cycle capture in the G1 stage is joined by Cyclin D1 down-regulation. Of note, ES blocks the proliferation and organization of endothelial cells into new blood vessels, and in animal studies, ES also inhibits angiogenesis and the growth of both primary tumors and secondary metastasis. ES was initially identified by its capacity to inhibit tumor angiogenesis in vitro and also in vivo. It can also be found in both healthy and patient’ serum, and has been detected in peripheral circulation. ES could be an attractive, non-invasive prognostic marker for some diseases, notably PAH. Therefore, the presented work is aimed at investigating the ES level in blood serum as a biomarker for detection, diagnosis and early treatment of PAH patients. In doing so, the association is ascertained between gender, age, body mass index (BMI), waist circumferences, smoking, types of PAH (primary and secondary) and this potential biomarker is assessed in PAH patients.
6. Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. Journal of the American College of Cardiology. J Am Coll Cardiol. 2004; 43(12):5S-12S.
7. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013; 62(25):D34-D41.
8. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1): S20-S31.
9. Toshner M, Tajsic T, Morrell NW. Pulmonary hypertension: advances in pathogenesis and treatment. Br Med Bull. 2010;94(1):21-32.
10. Eddahibi S, Morrell N, d’Ortho MP, Naeije R, Adnot S. Pathobiology of pulmonary arterial hypertension. Eur Respir J. 2002;20(6): 1559-72.
11. Ihida-Stansbury K, McKean DM, Lane KB, Loyd JE, Wheeler LA, Morrell NW, et al. Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. Am J Physiol. Lung Cell. Mol Physiol. 2006;291(4):L694-702.
12. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2):277-85.
13. Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins. Proc Natl Acad Sci U S A. 2003;100(8):4766-71.
18. Hohenester E, Sasaki T, Olsen BR, Timpl R. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 Å resolution. EMBO J. 1998;17(6):1656-64.
19. Dixelius J, Cross MJ, Matsumoto T, Claesson-Welsh L. Endostatin action and intracellular signaling: β-catenin as a potential target? Cancer Letters. 2003;196(1):1-2.
20. Kreuger J, Matsumoto T, Vanwildemeersch M, Sasaki T, Timpl R, Claesson‐Welsh L, et al. Role of heparan sulfate domain organization in endostatin inhibition of endothelial cell function. EMBO J. 2002; 21(23):6303-11.
21. Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J. 2000;19(6):1187-94.
22. Sipola A. Effects of Vascular Endothelial Growth Factor (VEGF-A) And Endostatin On Bone. Finland: Ph D Thesis, Univ Ouluensis 2009: 108pp.
23. Belur LR, Podetz-Pedersen KM, Sorenson BS, Hsu AH, Parker JB, Carlson CS, et al. Inhibition of angiogenesis and suppression of colorectal cancer metastatic to the liver using the Sleeping Beauty Transposon System. Mol Cancer. 2011;10(1):14.
24. Jing Y, Lu H, Wu K, Subramanian IV, Ramakrishnan S. Inhibition of ovarian cancer by RGD‐P125A‐endostatin‐Fc fusion proteins. Int J Cancer. 2011;129(3):751-61.
25. Shin SU, Cho HM, Merchan JR, Zhang J, Kovacs K, Jing Y, et al. Targeted delivery of an antibody-mutant human endostatin fusion protein results in enhanced anti-tumor efficacy. Mol Cancer Ther. 2011;10(4):603-614.
26. Tysome JR, Briat A, Alusi G, Cao F, Gao D, Yu J, et. al. Lister strain of vaccinia virus armed with endostatin–angiostatin fusion gene as a novel therapeutic agent for human pancreatic cancer. Gene Ther. 2009;16(10):1223.
27. Tysome JR, Wang P, Alusi G, Briat A, Gangeswaran R, Wang J, et al. Lister Vaccine Strain of Vaccinia Virus Armed with the Endostatin– Angiostatin Fusion Gene: An Oncolytic Virus Superior to dl 1520 (ONYX-015) for Human Head and Neck Cancer. Hum Gene Ther. 2011;22(9):1101-8.
28. Ho AS, Chen CH, Cheng CC, Wang CC, Lin HC, Luo TY, et al. Neutrophil elastase as a diagnostic marker and therapeutic target in colorectal cancers. Oncotarget. 2014;5(2):473-80.
29. Reiseter S, Molberg Ø, Gunnarsson R, Lund MB, Aalokken TM, Aukrust P, et al. Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study. Arthritis Res Ther. 2015;17(1):231.
30. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66(7):940-4.
31. Viswanath V, Phiske MM, Gopalani VV. Systemic sclerosis: current concepts in pathogenesis and therapeutic aspects of dermatological manifestations. Indian J Dermatol. 2013;58(4):255-268.
32. Murray LA, Rubinowitz A, Herzog EL. Interstitial lung disease: is interstitial lung disease the same as scleroderma lung disease? Curr Opin Rheumatol. 2012;24(6):656-62.
33. Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease. Matrix Biol. 2011;30(2):83-92.
34. Flåm ST, Gunnarsson R, Garen T, Norwegian MCTD Study Group, Lie BA, Molberg Ø. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. Rheumatology. 2014;54(3):528-35.
35. Anwar A, Ruffenach G, Mahajan A, Eghbali M, Umar S. Novel biomarkers for pulmonary arterial hypertension. Respir Res. 2016; 17(1):88.
36. Damico R, Kolb TM, Valera L, Wang L, Housten T, Tedford RJ, et al. Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;191(2):208-18.
37. Färkkilä A. Molecular Studies on Pathogenesis, Prognostic Factors, and New Treatment Options for Ovarian Granulosa Cell Tumors. Finland: Ph D Thesis, Univ Helsinki 2012: 86pp.
38. Freedman DS, Horlick M, Berenson GS. A comparison of the Slaughter skinfold-thickness equations and BMI in predicting body fatness and cardiovascular disease risk factor levels in children 1-4. Am J Clin Nutr. 2013;98(6):1417-24.
39. Rothberg AE, McEwen LN, Kraftson AT, Ajluni N, Fowler CE, Nay CK, et al. Impact of weight loss on waist circumference and the components of the metabolic syndrome. BMJ Open Diabetes Res Care. 2017;5(1):e000341.
40. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2015;37(1):67-119.
41. Alhabeeb W, Idrees MM, Ghio S, Kashour T. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary hypertension due to left heart disease. Ann Thorac Med. 2014;9(Suppl 1):S47-S55.
42. McNeil K, Dunning J, Morrell NW. The pulmonary physician in critical care• 13: The pulmonary circulation and right ventricular failure in the ITU. Thorax. 2003;58(2):157-62.
43. Marek-Trzonkowska N, Kwieczyńska A, Reiwer-Gostomska M, Koliński T, Molisz A, Siebert J. Arterial hypertension is characterized by imbalance of pro-angiogenic versus anti-angiogenic factors. PLoS ONE. 2015;10(5):e0126190.
44. Gouya G, Siller-Matula JM, Fritzer-Szekeres M, Neuhold S, Storka A, Neuhofer LM, et al. Association of endostatin with mortality in patients with chronic heart failure. Eur J Clin Invest. 2014;44(2): 125-35.
45. Galambos C, Minic AD, Bush D, Nguyen D, Dodson B, Seedorf G, et al. Increased lung expression of anti-angiogenic factors in down syndrome: potential role in abnormal lung vascular growth and the risk for pulmonary hypertension. PLoS ONE. 2016;11(8):e0159005.
46. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-87.
47. Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med. 2009;179(9): 835-42.
48. White K, Johansen AK, Nilsen M, Ciuclan L, Wallace E, Paton L, et al. Activity of the estrogen metabolising enzyme cytochrome P450 1B1 influences the development of pulmonary arterial hypertension. Circulation. 2012;126(9):1087-98.
49. Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, et al. Alterations in estrogen metabolism: Implications for higher penetrance of FPAH in females. Eur Respir J. 2009;34(5):1093-99.
50. Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, et al. 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor–mediated effects. Am J Respir Crit Care Med. 2012;185(9):965-80.
51. Asai K, Kanazawa H, Otani K, Shiraishi S, Hirata K, Yoshikawa J. Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects. J Allergy Clin. Immunol. 2002;110(4):571-5.
52. Ling Y, Johnson MK, Kiely DG, Condliffe R, Elliot CA, Gibbs JS, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012;186(8):790-6.
53. Weissmann N, Tadić A, Hänze J, Rose F, Winterhalder S, Nollen M, et al. Hypoxic vasoconstriction in intact lungs: a role for NADPH oxidase-derived H2O2? Am J Physiol Lung Cell Mol Physiol. 2000; 279(4):L683-90.
54. Michelakis ED, Rebeyka I, Wu X, Nsair A, Thébaud B, Hashimoto K, et al. O2 Regulation of Voltage-gated K+ Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor. 2: Regulation of Voltage-gated K+ Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor Sensing in the Human Ductus Arteriosus: Regulation of Voltage-gated K+ Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor. Cir Res: J Amer Heart Assoc. 2002;91(6): 478-86.
55. Zhao L, Wang J, Wang L, Liang YT, Chen YQ, Lu WJ, et al. Remodeling of rat pulmonary artery induced by chronic smoking exposure. J Thorac Dis. 2014;6(6):818.
56. Wright JL, Tai H, Wang R, Wang X, Churg A. Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-α signaling. Am. J Physiol Lung Cell Mol Physiol. 2007;292(1):L125-33.
57. Mitsuma W, Kodama M, Hanawa H, Ito M, Ramadan MM, Hirono S, et al. Serum endostatin in the coronary circulation of patients with coronary heart disease and its relation to coronary collateral formation. Am J Physiol Heart Circ. Physiol. 2007;99(4):494-8.
58. Sodha NR, Clements RT, Boodhwani M, Xu SH, Laham RJ, Bianchi C, et al. Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation. Am J Physiol Heart Circ Physiol. 2009;296(2): H428-34.
59. Kessler R, Faller M, Weitzenblum E, Chaouat A, Aykut A, DucolonÉ A, et al. “Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med. 2001;164(2):219-24.
60. Nilsson I, Shibuya M, Wennström S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res. 2004;299(2):476-85.
61. Santos S, Peinado VI, Ramirez J, Melgosa T, Roca J, Rodriguez-Roisin R, et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J. 2002;19(4): 632-8.
62. Menzel O, Bekkeheien RC, Reymond A, Fukai N, Boye E, Kosztolanyi G, et al. Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin. Hum Mutat. 2004;23(1):77-84.
63. Vogel-Claussen J, Skrok J, Shehata ML, Singh S, Sibley CT, Boyce DM, et al. Right and left ventricular myocardial perfusion reserves correlate with right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension. Radiol. 2011;258(1):119-27.
64. Ashwell M, Gibson S. Waist-to-height ratio as an indicator of ‘early health risk’: simpler and more predictive than using a ‘matrix’based on BMI and waist circumference. BMJ Open. 2016;6(3):e010159.
65. Hammod HJ, Al-Dujaili AN, NooriAl-Dujaili M. Relationship Between Adipocyte Fatty Acid-Binding Protein In Obese Men With Cardiovascular Diseases. Res J Pharm Biol Chem Sci. 2016;7(3):804-8.
66. Hammod HJ, Al-Dujaili AN, Al-Dujaili MN. The Correlation between Cardiovascular Diseases in Obese Men with The Inflammatory Markers: Dyslipidemia, C-Reactive Protein and Tumor Necrosis Factor-alpha. Res J Pharm Biol Chem Sci. 2016;7(3):809-14.
67. Taichman DB, Mandel J. Epidemiology of pulmonary arterial hypertension. Clin Chest Med. 2007;28(1):1-22.
68. Lau EM, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017;14(10):603.
69. Burger CD, Foreman AJ, Miller DP, Safford RE, McGoon MD, Badesch DB. Comparison of body habitus in patients with pulmonary arterial hypertension enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management with normative values from the National Health and Nutrition Examination Survey. Mayo Clin Proc. 2011;86(2):105-112.
70. Taraseviciute A, Voelkel NF. Severe pulmonary hypertension in postmenopausal obese women. Eur J Med Res. 2006;11(5):198-202.
71. Leone N, Courbon D, Thomas F, Bean K, Jégo B, Leynaert B, et al. Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med. 2009;179(6):509-16.
72. Zeng WJ, Sun YJ, Gu Q, Xiong CM, Li JJ, He JG. The impact of pulmonary arterial hypertension-targeted therapy on survival in Chinese patients with idiopathic pulmonary arterial hypertension. Pulm Circ. 2012;2(3):373-8.