Carotuximab effects on endoglin expression and signaling in liver fibrosis

• Název práce v češtině: Účinky Carotuximabu na expresi a signalizaci endoglinu při fibróze jater
• Název v anglickém jazyce: Carotuximab effects on endoglin expression and signaling in liver fibrosis
• Akademický rok vypsání: 2021/2022
• Typ práce: rigorózní práce
• Jazyk práce: angličtina
• Ústav: Katedra biologických a lékařských věd (16-16150)
• Vedoucí / školitel: prof. PharmDr. Petr Nachtigal, Ph.D.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 22.07.2022
• Datum zadání: 22.07.2022
• Datum potvrzení stud. oddělením: 22.07.2022
• Datum a čas obhajoby: 24.03.2023 00:00
• Datum odevzdání elektronické podoby: 15.03.2023
• Datum proběhlé obhajoby: 24.03.2023
• Oponenti: PharmDr. Jana Urbánková Rathouská, Ph.D.

Zásady pro vypracování

Literární rešerše
Western blot analýza vybraných proteinů
Sepsání diplomové práce

Seznam odborné literatury

1. Oujo B, Perez-Barriocanal F, Bernabeu C, Lopez-Novoa JM (2013) Membrane and soluble forms of endoglin in preeclampsia. Curr Mol Med 13 (8):1345-1357
2. Bot PT, Hoefer IE, Sluijter JP, van Vliet P, Smits AM, Lebrin F, Moll F, de Vries JP, Doevendans P, Piek JJ, Pasterkamp G, Goumans MJ (2009) Increased expression of the transforming growth factor-beta signaling pathway, endoglin, and early growth response-1 in stable plaques. Stroke 40 (2):439-447. doi:STROKEAHA.108.522284 [pii]
10.1161/STROKEAHA.108.522284
3. St-Jacques S, Forte M, Lye SJ, Letarte M (1994) Localization of endoglin, a transforming growth factor-beta binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy. Biol Reprod 51 (3):405-413
4. Meurer S, Wimmer AE, Leur EV, Weiskirchen R (2019) Endoglin Trafficking/Exosomal Targeting in Liver Cells Depends on N-Glycosylation. Cells 8 (9). doi:10.3390/cells8090997
5. Lastres P, Bellon T, Cabanas C, Sanchez-Madrid F, Acevedo A, Gougos A, Letarte M, Bernabeu C (1992) Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen. Eur J Immunol 22 (2):393-397
6. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, et al. (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8 (4):345-351. doi:10.1038/ng1294-345
7. Kapur NK, Morine KJ, Letarte M (2013) Endoglin: a critical mediator of cardiovascular health. Vasc Health Risk Manag 9:195-206. doi:10.2147/VHRM.S29144
8. Qu R, Silver MM, Letarte M (1998) Distribution of endoglin in early human development reveals high levels on endocardial cushion tissue mesenchyme during valve formation. Cell Tissue Res 292 (2):333-343
9. Alsamman M, Sterzer V, Meurer SK, Sahin H, Schaeper U, Kuscuoglu D, Strnad P, Weiskirchen R, Trautwein C, Scholten D (2018) Endoglin in human liver disease and murine models of liver fibrosis-A protective factor against liver fibrosis. Liver Int 38 (5):858-867. doi:10.1111/liv.13595
10. Vicen M, Vitverova B, Havelek R, Blazickova K, Machacek M, Rathouska J, Najmanova I, Dolezelova E, Prasnicka A, Sternak M, Bernabeu C, Nachtigal P (2019) Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro. FASEB J 33 (5):6099-6114. doi:10.1096/fj.201802245R
11. Rossi E, Sanz-Rodriguez F, Eleno N, Duwell A, Blanco FJ, Langa C, Botella LM, Cabanas C, Lopez-Novoa JM, Bernabeu C (2013) Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration. Blood 121 (2):403-415. doi:10.1182/blood-2012-06-435347
blood-2012-06-435347 [pii]
12. Aristorena M, Gallardo-Vara E, Vicen M, de Las Casas-Engel M, Ojeda-Fernandez L, Nieto C, Blanco FJ, Valbuena-Diez AC, Botella LM, Nachtigal P, Corbi AL, Colmenares M, Bernabeu C (2019) MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells. Int J Mol Sci 20 (12). doi:10.3390/ijms20123107
13. Hawinkels LJ, Kuiper P, Wiercinska E, Verspaget HW, Liu Z, Pardali E, Sier CF, ten Dijke P (2010) Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res 70 (10):4141-4150. doi:0008-5472.CAN-09-4466 [pii]
10.1158/0008-5472.CAN-09-4466
14. Valbuena-Diez AC, Blanco FJ, Oujo B, Langa C, Gonzalez-Nunez M, Llano E, Pendas AM, Diaz M, Castrillo A, Lopez-Novoa JM, Bernabeu C (2012) Oxysterol-induced soluble endoglin release and its involvement in hypertension. Circulation 126 (22):2612-2624. doi:10.1161/CIRCULATIONAHA.112.101261
15. Blaha M, Cermanova M, Blaha V, Jarolim P, Andrys C, Blazek M, Maly J, Smolej L, Zajic J, Masin V, Zimova R, Rehacek V (2008) Elevated serum soluble endoglin (sCD105) decreased during extracorporeal elimination therapy for familial hypercholesterolemia. Atherosclerosis 197 (1):264-270. doi:S0021-9150(07)00261-4 [pii]
10.1016/j.atherosclerosis.2007.04.022
16. Blann AD, Wang JM, Wilson PB, Kumar S (1996) Serum levels of the TGF-beta receptor are increased in atherosclerosis. Atherosclerosis 120 (1-2):221-226
17. Malhotra R, Paskin-Flerlage S, Zamanian RT, Zimmerman P, Schmidt JW, Deng DY, Southwood M, Spencer R, Lai CS, Parker W, Channick RN, Morrell NW, Elliott CG, Yu PB (2013) Circulating angiogenic modulatory factors predict survival and functional class in pulmonary arterial hypertension. Pulm Circ 3 (2):369-380. doi:10.4103/2045-8932.110445
18. Leanos-Miranda A, Navarro-Romero CS, Sillas-Pardo LJ, Ramirez-Valenzuela KL, Isordia-Salas I, Jimenez-Trejo LM (2019) Soluble Endoglin As a Marker for Preeclampsia, Its Severity, and the Occurrence of Adverse Outcomes. Hypertension 74 (4):991-997. doi:10.1161/HYPERTENSIONAHA.119.13348
19. Doghish AS, Bassyouni AA, Mahfouz MH, Abd El-Aziz HG, Zakaria RY (2019) Plasma endoglin in Type2 diabetic patients with nephropathy. Diabetes Metab Syndr 13 (1):764-768. doi:10.1016/j.dsx.2018.11.058
20. Rathouska J, Nemeckova I, Zemankova L, Strasky Z, Jezkova K, Varejckova M, Nachtigal P (2015) Cell adhesion molecules and eNOS expression in aorta of normocholesterolemic mice with different predispositions to atherosclerosis. Heart Vessels 30 (2):241-248. doi:10.1007/s00380-014-0493-8
21. Nachtigal P, Zemankova Vecerova L, Rathouska J, Strasky Z (2012) The role of endoglin in atherosclerosis. Atherosclerosis 224 (1):4-11. doi:10.1016/j.atherosclerosis.2012.03.001
22. Schoonderwoerd MJA, Goumans MTH, Hawinkels L (2020) Endoglin: Beyond the Endothelium. Biomolecules 10 (2). doi:10.3390/biom10020289
23. Xu G, Barrios-Rodiles M, Jerkic M, Turinsky AL, Nadon R, Vera S, Voulgaraki D, Wrana JL, Toporsian M, Letarte M (2014) Novel protein interactions with endoglin and activin receptor-like kinase 1: potential role in vascular networks. Molecular & cellular proteomics : MCP 13 (2):489-502. doi:10.1074/mcp.M113.033464
24. Gougos A, Letarte M (1990) Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 265 (15):8361-8364
25. Llorca O, Trujillo A, Blanco FJ, Bernabeu C (2007) Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. J Mol Biol 365 (3):694-705
26. Velasco S, Alvarez-Munoz P, Pericacho M, Dijke PT, Bernabeu C, Lopez-Novoa JM, Rodriguez-Barbero A (2008) L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci 121 (Pt 6):913-919. doi:jcs.023283 [pii]
10.1242/jcs.023283
27. Blanco FJ, Grande MT, Langa C, Oujo B, Velasco S, Rodriguez-Barbero A, Perez-Gomez E, Quintanilla M, Lopez-Novoa JM, Bernabeu C (2008) S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology. Circ Res 103 (12):1383-1392. doi:CIRCRESAHA.108.176552 [pii]
10.1161/CIRCRESAHA.108.176552
28. Conley BA, Smith JD, Guerrero-Esteo M, Bernabeu C, Vary CP (2000) Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis 153 (2):323-335. doi:S0021915000004226 [pii]
29. Davignon J, Ganz P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109 (23 Suppl 1):III27-32
30. Jerkic M, Rivas-Elena JV, Prieto M, Carron R, Sanz-Rodriguez F, Perez-Barriocanal F, Rodriguez-Barbero A, Bernabeu C, Lopez-Novoa JM (2004) Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J 18 (3):609-611. doi:10.1096/fj.03-0197fje
03-0197fje [pii]
31. Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M, Letarte M (2005) A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res 96 (6):684-692. doi:01.RES.0000159936.38601.22 [pii]
10.1161/01.RES.0000159936.38601.22
32. Santibanez JF, Letamendia A, Perez-Barriocanal F, Silvestri C, Saura M, Vary CP, Lopez-Novoa JM, Attisano L, Bernabeu C (2007) Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol 210 (2):456-468
33. Zemankova L, Varejckova M, Dolezalova E, Fikrova P, Jezkova K, Rathouska J, Cerveny L, Botella LM, Bernabeu C, Nemeckova I, Nachtigal P (2015) Atorvastatin-induced endothelial nitric oxide synthase expression in endothelial cells is mediated by endoglin. J Physiol Pharmacol 66 (3):403-413
34. Jerkic M, Letarte M (2015) Increased endothelial cell permeability in endoglin-deficient cells. FASEB J 29 (9):3678-3688. doi:10.1096/fj.14-269258
35. Anderberg C, Cunha SI, Zhai Z, Cortez E, Pardali E, Johnson JR, Franco M, Paez-Ribes M, Cordiner R, Fuxe J, Johansson BR, Goumans MJ, Casanovas O, ten Dijke P, Arthur HM, Pietras K (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210 (3):563-579. doi:10.1084/jem.20120662
36. Rossini R, Capodanno D, Ferrero P, Gargiulo G, Capranzano P (2016) Management issues of chronic therapy with non-vitamin K oral anticoagulants or antiplatelet agents: Different or alike? Int J Cardiol 221:695-696. doi:10.1016/j.ijcard.2016.07.008
37. Ojeda-Fernandez L, Recio-Poveda L, Aristorena M, Lastres P, Blanco FJ, Sanz-Rodriguez F, Gallardo-Vara E, de las Casas-Engel M, Corbi A, Arthur HM, Bernabeu C, Botella LM (2016) Mice Lacking Endoglin in Macrophages Show an Impaired Immune Response. PLoS Genet 12 (3):e1005935. doi:10.1371/journal.pgen.1005935
38. Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabeu C (2002) Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 100 (12):4001-4010. doi:10.1182/blood.V100.12.4001
100/12/4001 [pii]
39. Gallardo-Vara E, Blanco FJ, Roque M, Friedman SL, Suzuki T, Botella LM, Bernabeu C (2016) Transcription factor KLF6 upregulates expression of metalloprotease MMP14 and subsequent release of soluble endoglin during vascular injury. Angiogenesis 19 (2):155-171. doi:10.1007/s10456-016-9495-8
40. Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C (2002) Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem 277 (46):43799-43808. doi:10.1074/jbc.M207160200
M207160200 [pii]
41. van Uden P, Kenneth NS, Rocha S (2008) Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J 412 (3):477-484. doi:10.1042/BJ20080476
42. Henry-Berger J, Mouzat K, Baron S, Bernabeu C, Marceau G, Saru JP, Sapin V, Lobaccaro JM, Caira F (2008) Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR. Biol Reprod 78 (6):968-975. doi:10.1095/biolreprod.107.066498
43. Csanyi G, Gajda M, Franczyk-Zarow M, Kostogrys R, Gwozdz P, Mateuszuk L, Sternak M, Wojcik L, Zalewska T, Walski M, Chlopicki S (2012) Functional alterations in endothelial NO, PGI(2) and EDHF pathways in aorta in ApoE/LDLR-/- mice. Prostaglandins & other lipid mediators 98 (3-4):107-115. doi:10.1016/j.prostaglandins.2012.02.002
44. Vecerova L, Strasky Z, Rathouska J, Slanarova M, Brcakova E, Micuda S, Nachtigal P (2012) Activation of TGF-beta receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice. J Atheroscler Thromb 19 (2):115-126
45. Strasky Z, Vecerova L, Rathouska J, Slanarova M, Brcakova E, Kudlackova Z, Andrys C, Micuda S, Nachtigal P (2011) Cholesterol effects on endoglin and its downstream pathways in ApoE/LDLR double knockout mice. Circ J 75 (7):1747-1755
46. Rathouska J, Vecerova L, Strasky Z, Slanarova M, Brcakova E, Mullerova Z, Andrys C, Micuda S, Nachtigal P (2011) Endoglin as a possible marker of atorvastatin treatment benefit in atherosclerosis. Pharmacol Res 64 (1):53-59. doi:10.1016/j.phrs.2011.03.008
47. Alvarez-Munoz P, Mauer M, Kim Y, Rich SS, Miller ME, Russell GB, Lopez-Novoa JM, Caramori ML (2010) Cellular basis of diabetic nephropathy: V. Endoglin expression levels and diabetic nephropathy risk in patients with Type 1 diabetes. J Diabetes Complications 24 (4):242-249. doi:10.1016/j.jdiacomp.2009.03.004
48. La Sala L, Pujadas G, De Nigris V, Canivell S, Novials A, Genovese S, Ceriello A (2015) Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress. Acta Diabetol 52 (3):505-512. doi:10.1007/s00592-014-0670-3
49. Wang S, Hirschberg R (2009) Diabetes-relevant regulation of cultured blood outgrowth endothelial cells. Microvasc Res 78 (2):174-179. doi:10.1016/j.mvr.2009.06.002
50. Rinella ME (2015) Nonalcoholic fatty liver disease: a systematic review. Jama 313 (22):2263-2273. doi:10.1001/jama.2015.5370
51. Finnson KW, Philip A (2012) Endoglin in liver fibrosis. J Cell Commun Signal 6 (1):1-4. doi:10.1007/s12079-011-0154-y
52. Garcia-Pozo L, Miquilena-Colina ME, Lozano-Rodriguez T, Garcia-Monzon C (2008) [Endoglin: structure, biological functions, and role in fibrogenesis]. Rev Esp Enferm Dig 100 (6):355-360. doi:10.4321/s1130-01082008000600008
53. Meurer SK, Tihaa L, Borkham-Kamphorst E, Weiskirchen R (2011) Expression and functional analysis of endoglin in isolated liver cells and its involvement in fibrogenic Smad signalling. Cell Signal 23 (4):683-699. doi:10.1016/j.cellsig.2010.12.002
54. Meurer SK, Alsamman M, Scholten D, Weiskirchen R (2014) Endoglin in liver fibrogenesis: Bridging basic science and clinical practice. World J Biol Chem 5 (2):180-203. doi:10.4331/wjbc.v5.i2.180
55. Chan DC, Barrett HP, Watts GF (2004) Dyslipidemia in visceral obesity: mechanisms, implications, and therapy. Am J Cardiovasc Drugs 4 (4):227-246
56. Kurki E, Shi J, Martonen E, Finckenberg P, Mervaala E (2012) Distinct effects of calorie restriction on adipose tissue cytokine and angiogenesis profiles in obese and lean mice. Nutr Metab (Lond) 9 (1):64. doi:10.1186/1743-7075-9-64
57. Jilkova ZM, Hensler M, Medrikova D, Janovska P, Horakova O, Rossmeisl M, Flachs P, Sell H, Eckel J, Kopecky J (2014) Adipose tissue-related proteins locally associated with resolution of inflammation in obese mice. Int J Obes (Lond) 38 (2):216-223. doi:10.1038/ijo.2013.108
58. Vanlaere I, Libert C (2009) Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock. Clin Microbiol Rev 22 (2):224-239, Table of Contents. doi:10.1128/CMR.00047-08
59. Vandenbroucke RE, Libert C (2014) Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 13 (12):904-927. doi:10.1038/nrd4390
60. Klein T, Bischoff R (2011) Physiology and pathophysiology of matrix metalloproteases. Amino Acids 41 (2):271-290. doi:10.1007/s00726-010-0689-x
61. Feinberg MW, Jain MK, Werner F, Sibinga NE, Wiesel P, Wang H, Topper JN, Perrella MA, Lee ME (2000) Transforming growth factor-beta 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. J Biol Chem 275 (33):25766-25773. doi:10.1074/jbc.M002664200
62. Rajavashisth TB, Xu XP, Jovinge S, Meisel S, Xu XO, Chai NN, Fishbein MC, Kaul S, Cercek B, Sharifi B, Shah PK (1999) Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation 99 (24):3103-3109. doi:10.1161/01.cir.99.24.3103
63. Rathouska J, Jezkova K, Nemeckova I, Nachtigal P (2015) Soluble endoglin, hypercholesterolemia and endothelial dysfunction. Atherosclerosis 243 (2):383-388. doi:10.1016/j.atherosclerosis.2015.10.003
64. Li Q, Lin F, Ke D, Cheng Q, Gui Y, Zhou Y, Wu Y, Wang Y, Zhu P (2020) Combination of Endoglin and ASCVD Risk Assessment Improves Carotid Subclinical Atherosclerosis Recognition. J Atheroscler Thromb 27 (4):331-341. doi:10.5551/jat.50898
65. Saita E, Miura K, Suzuki-Sugihara N, Miyata K, Ikemura N, Ohmori R, Ikegami Y, Kishimoto Y, Kondo K, Momiyama Y (2017) Plasma Soluble Endoglin Levels Are Inversely Associated With the Severity of Coronary Atherosclerosis-Brief Report. Arterioscler Thromb Vasc Biol 37 (1):49-52. doi:10.1161/ATVBAHA.116.308494
66. Charytan DM, Cinelli A, Zeisberg EM (2015) Association of circulating angiogenesis inhibitors and asymmetric dimethyl arginine with coronary plaque burden. Fibrogenesis Tissue Repair 8:13. doi:10.1186/s13069-015-0029-6
67. Blazquez-Medela AM, Garcia-Ortiz L, Gomez-Marcos MA, Recio-Rodriguez JI, Sanchez-Rodriguez A, Lopez-Novoa JM, Martinez-Salgado C (2010) Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Med 8:86. doi:10.1186/1741-7015-8-86
68. Bilir B, Ekiz Bilir B, Yilmaz I, Soysal Atile N, Yildirim T, Kara SP, Gumustas SA, Orhan AE, Aydin M (2016) Association of apelin, endoglin and endocan with diabetic peripheral neuropathy in type 2 diabetic patients. Eur Rev Med Pharmacol Sci 20 (5):892-898
69. Ekiz-Bilir B, Bilir B, Aydin M, Soysal-Atile N (2019) Evaluation of endocan and endoglin levels in chronic kidney disease due to diabetes mellitus. Arch Med Sci 15 (1):86-91. doi:10.5114/aoms.2018.79488
70. Ceriello A, La Sala L, De Nigris V, Pujadas G, Testa R, Uccellatore A, Genovese S (2015) GLP-1 reduces metalloproteinase-14 and soluble endoglin induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Endocrine 50 (2):508-511. doi:10.1007/s12020-015-0565-2
71. Cawyer C, Afroze SH, Drever N, Allen S, Jones R, Zawieja DC, Kuehl T, Uddin MN (2016) Attenuation of hyperglycemia-induced apoptotic signaling and anti-angiogenic milieu in cultured cytotrophoblast cells. Hypertens Pregnancy 35 (2):159-169. doi:10.3109/10641955.2015.1122035
72. Cawyer CR, Horvat D, Leonard D, Allen SR, Jones RO, Zawieja DC, Kuehl TJ, Uddin MN (2014) Hyperglycemia impairs cytotrophoblast function via stress signaling. Am J Obstet Gynecol 211 (5):541 e541-548. doi:10.1016/j.ajog.2014.04.033
73. Lappas M (2014) Markers of endothelial cell dysfunction are increased in human omental adipose tissue from women with pre-existing maternal obesity and gestational diabetes. Metabolism: clinical and experimental 63 (6):860-873. doi:10.1016/j.metabol.2014.03.007
74. Vieira MC, Poston L, Fyfe E, Gillett A, Kenny LC, Roberts CT, Baker PN, Myers JE, Walker JJ, McCowan LM, North RA, Pasupathy D, Consortium S (2017) Clinical and biochemical factors associated with preeclampsia in women with obesity. Obesity (Silver Spring) 25 (2):460-467. doi:10.1002/oby.21715
75. Coral-Alvarado PX, Garces MF, Caminos JE, Iglesias-Gamarra A, Restrepo JF, Quintana G (2010) Serum endoglin levels in patients suffering from systemic sclerosis and elevated systolic pulmonary arterial pressure. Int J Rheumatol 2010. doi:10.1155/2010/969383
76. Bakouboula B, Morel O, Faure A, Zobairi F, Jesel L, Trinh A, Zupan M, Canuet M, Grunebaum L, Brunette A, Desprez D, Chabot F, Weitzenblum E, Freyssinet JM, Chaouat A, Toti F (2008) Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. Am J Respir Crit Care Med 177 (5):536-543. doi:10.1164/rccm.200706-840OC
77. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12 (6):642-649. doi:nm1429 [pii]
10.1038/nm1429
78. Walshe TE, Dole VS, Maharaj AS, Patten IS, Wagner DD, D'Amore PA (2009) Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling. Arterioscler Thromb Vasc Biol 29 (8):1185-1192. doi:ATVBAHA.109.186742 [pii]
10.1161/ATVBAHA.109.186742
79. Varejckova M, Gallardo-Vara E, Vicen M, Vitverova B, Fikrova P, Dolezelova E, Rathouska J, Prasnicka A, Blazickova K, Micuda S, Bernabeu C, Nemeckova I, Nachtigal P (2017) Soluble endoglin modulates the proinflammatory mediators NF-kappaB and IL-6 in cultured human endothelial cells. Life Sci 175:52-60. doi:10.1016/j.lfs.2017.03.014
80. Kapur NK, Wilson S, Yunis AA, Qiao X, Mackey E, Paruchuri V, Baker C, Aronovitz MJ, Karumanchi SA, Letarte M, Kass DA, Mendelsohn ME, Karas RH (2012) Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure. Circulation 125 (22):2728-2738. doi:10.1161/CIRCULATIONAHA.111.080002
81. Munoz-Felix JM, Gonzalez-Nunez M, Lopez-Novoa JM (2013) ALK1-Smad1/5 signaling pathway in fibrosis development: friend or foe? Cytokine Growth Factor Rev 24 (6):523-537. doi:10.1016/j.cytogfr.2013.08.002
82. Pannu J, Nakerakanti S, Smith E, ten Dijke P, Trojanowska M (2007) Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J Biol Chem 282 (14):10405-10413. doi:10.1074/jbc.M611742200
83. Wiercinska E, Wickert L, Denecke B, Said HM, Hamzavi J, Gressner AM, Thorikay M, ten Dijke P, Mertens PR, Breitkopf K, Dooley S (2006) Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells. Hepatology 43 (5):1032-1041. doi:10.1002/hep.21135
84. Dituri F, Cossu C, Mancarella S, Giannelli G (2019) The Interactivity between TGFbeta and BMP Signaling in Organogenesis, Fibrosis, and Cancer. Cells 8 (10). doi:10.3390/cells8101130
85. Breitkopf-Heinlein K, Meyer C, Konig C, Gaitantzi H, Addante A, Thomas M, Wiercinska E, Cai C, Li Q, Wan F, Hellerbrand C, Valous NA, Hahnel M, Ehlting C, Bode JG, Muller-Bohl S, Klingmuller U, Altenoder J, Ilkavets I, Goumans MJ, Hawinkels LJ, Lee SJ, Wieland M, Mogler C, Ebert MP, Herrera B, Augustin H, Sanchez A, Dooley S, Ten Dijke P (2017) BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut 66 (5):939-954. doi:10.1136/gutjnl-2016-313314
86. Lawera A, Tong Z, Thorikay M, Redgrave RE, Cai J, van Dinther M, Morrell NW, Afink GB, Charnock-Jones DS, Arthur HM, Ten Dijke P, Li W (2019) Role of soluble endoglin in BMP9 signaling. Proc Natl Acad Sci U S A 116 (36):17800-17808. doi:10.1073/pnas.1816661116
87. Ruiz-Remolina L, Ollauri-Ibanez C, Perez-Roque L, Nunez-Gomez E, Perez-Barriocanal F, Lopez-Novoa JM, Pericacho M, Rodriguez-Barbero A (2017) Circulating soluble endoglin modifies the inflammatory response in mice. PloS one 12 (11):e0188204. doi:10.1371/journal.pone.0188204
88. Nemeckova I, Serwadczak A, Oujo B, Jezkova K, Rathouska J, Fikrova P, Varejckova M, Bernabeu C, Lopez-Novoa JM, Chlopicki S, Nachtigal P (2015) High soluble endoglin levels do not induce endothelial dysfunction in mouse aorta. PloS one 10 (3):e0119665. doi:10.1371/journal.pone.0119665
89. Jezkova K, Rathouska J, Nemeckova I, Fikrova P, Dolezelova E, Varejckova M, Vitverova B, Tysonova K, Serwadczak A, Buczek E, Bernabeu C, Lopez-Novoa JM, Chlopicki S, Nachtigal P (2016) High Levels of Soluble Endoglin Induce a Proinflammatory and Oxidative-Stress Phenotype Associated with Preserved NO-Dependent Vasodilatation in Aortas from Mice Fed a High-Fat Diet. J Vasc Res 53 (3-4):149-162. doi:10.1159/000448996
90. Gallardo-Vara E, Gamella-Pozuelo L, Perez-Roque L, Bartha JL, Garcia-Palmero I, Casal JI, Lopez-Novoa JM, Pericacho M, Bernabeu C (2020) Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4. Cells 9 (4). doi:10.3390/cells9040988
91. Vitverova B, Blazickova K, Najmanova I, Vicen M, Hyspler R, Dolezelova E, Nemeckova I, Tebbens JD, Bernabeu C, Pericacho M, Nachtigal P (2018) Soluble endoglin and hypercholesterolemia aggravate endothelial and vessel wall dysfunction in mouse aorta. Atherosclerosis 271:15-25. doi:10.1016/j.atherosclerosis.2018.02.008
92. Dolezelova E, Sa ICI, Prasnicka A, Hroch M, Hyspler R, Ticha A, Lastuvkova H, Cermanova J, Pericacho M, Visek J, Lasticova M, Micuda S, Nachtigal P (2019) High soluble endoglin levels regulate cholesterol homeostasis and bile acids turnover in the liver of transgenic mice. Life Sci 232:116643. doi:10.1016/j.lfs.2019.116643
93. Nachtigal P, Pospisilova N, Vecerova L, Micuda S, Brcakova E, Pospechova K, Semecky V (2009) Atorvastatin Increases Endoglin, SMAD2, Phosphorylated SMAD2/3 and eNOS Expression in ApoE/LDLR Double Knockout Mice. J Atheroscler Thromb 16 (3):265-274
94. Giordano A, Romano S, Monaco M, Sorrentino A, Corcione N, Di Pace AL, Ferraro P, Nappo G, Polimeno M, Romano MF (2012) Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells. Am J Physiol Heart Circ Physiol 302 (1):H135-142. doi:10.1152/ajpheart.00490.2011
95. Zemankova L, Varejckova, M., Dolezelova, E., Fikrova, P., Jezkova, K., Rathouska, J., Cerveny, L., Botella, L.M., Bernabeu, C., Nemeckova, I., Nachtigal, P. (2015) Atorvastatin-induced endothelial nitric oxide synthase expression in endothelial cels is mediated by endoglin. Journal of Physiology and Pharmacology, vol 66.
96. Shyu KG, Wang BW, Chen WJ, Kuan P, Hung CR (2010) Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-beta1 in cultured cardiac fibroblasts. Eur J Heart Fail 12 (3):219-226. doi:10.1093/eurjhf/hfq011
97. Brownfoot FC, Tong S, Hannan NJ, Hastie R, Cannon P, Kaitu'u-Lino TJ (2016) Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta. BMC Pregnancy Childbirth 16:117. doi:10.1186/s12884-016-0902-3
98. Romero R, Erez O, Huttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, Pacora P, Yoon BH, Grossman LI (2017) Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 217 (3):282-302. doi:10.1016/j.ajog.2017.06.003
99. Buda V, Andor M, Baibata DE, Cozlac R, Radu G, Coricovac D, Danciu C, Ledeti I, Cheveresan A, Nica C, Tuduce P, Tomescu MC (2019) Decreased sEng plasma levels in hypertensive patients with endothelial dysfunction under chronic treatment with Perindopril. Drug Des Devel Ther 13:1915-1925. doi:10.2147/DDDT.S186378
100. Hannan NJ, Brownfoot FC, Cannon P, Deo M, Beard S, Nguyen TV, Palmer KR, Tong S, Kaitu'u-Lino TJ (2017) Resveratrol inhibits release of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin and improves vascular dysfunction - implications as a preeclampsia treatment. Scientific reports 7 (1):1819. doi:10.1038/s41598-017-01993-w
101. Liu Y, Tian H, Blobe GC, Theuer CP, Hurwitz HI, Nixon AB (2014) Effects of the combination of TRC105 and bevacizumab on endothelial cell biology. Invest New Drugs 32 (5):851-859. doi:10.1007/s10637-014-0129-y
102. Kumar S, Pan CC, Bloodworth JC, Nixon AB, Theuer C, Hoyt DG, Lee NY (2014) Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-beta signaling. Oncogene 33 (30):3970-3979. doi:10.1038/onc.2013.386

Předběžná náplň práce v anglickém jazyce

Literature review
Western blot analysis of proteins
Diploma Thesis writing