Journal of Literature Pharmacy Sciences

Vascular Functional Effects of the Apelinergic System
Apelinerjik Sistemin Vasküler Fonksiyonel Etkileri
Naciye İŞBİLa, Serdar ŞAHİNTÜRKa, Sadettin DEMİRELa
aDepartment of Physiology, Bursa Uludağ University Faculty of Medicine, Bursa, TURKEY
J Lit Pharm Sci. 2021;10(1):12-20
doi: 10.5336/pharmsci.2020-76153
Article Language: EN
Full Text
ABSTRACT
The apelinergic system consists of apelin, elabela, and their common receptor apelin receptor (APJ). APJ is a G protein-coupled receptor. Apelin is the first discovered endogenous APJ ligand. Later, elabela was discovered and added to the system. Apelinergic system components have a widespread expression in the human body. The apelinergic system which plays a role in many physiological processes such as body-fluid homeostasis, energy metabolism, and regulation of cardiac contractility participates in the regulation of vascular tone and blood pressure. Apelin and elabela, which have similar effects on vascular tone, differ in their effect mechanisms. APJ is expressed in both vascular endothelial cells and vascular smooth muscle cells. This situation is important because it mediates the opposite effects in vascular tension. Apelin usually has a vasodilator effect through the activation of the endothelial nitric oxide synthase/nitric oxide (NO) pathway in physiological conditions. However, in the absence of a functional endothelium, apelin causes vasoconstriction. Elabela has a vasodilator effect similar to apelin, but it is thought that NO has no role in the vasodilator effect of elabela. When apelin and elabela are administered peripherally, they usually lower blood pressure and exhibit an antihypertensive effect. Therefore, the apelinergic system has great potential to develop alternative agents for the treatment of hypertensive diseases such as essential hypertension and pulmonary hypertension. The half-lives of apelin and elabela are quite short, and current studies have focused on developing longer-acting apelinergic analogs. In this review, we focused on the vascular functional effects and effect mechanisms of the apelinergic system.

Keywords: Apelin; vasodilation; vasoconstriction; hypertension; elabela
ÖZET
Apelinerjik sistem apelin, elabela ve bunların ortak reseptörü apelin reseptörü (APJ)'nden oluşur. APJ, G-proteini kenetli bir reseptördür. Apelin, ilk keşfedilen endojen APJ ligandıdır. Daha sonra ise elabela keşfedilerek sisteme eklenmiştir. Apelinerjik sistem elemanları insan vücudunda yaygın ekspresyona sahiptir. Vücut-sıvı homeostazı, enerji metabolizması ve kardiyak kontraktilitenin düzenlenmesi gibi birçok fizyolojik süreçte rolü olan apelinerjik sistem, damar tonusunun ve kan basıncının düzenlenmesine de katılır. Damar tonusu üzerine benzer etkileri olan apelin ve elabela, etki mekanizmasında farklılık gösterir. APJ, hem damar endotel hücrelerinde hem de damar düz kas hücrelerinde eksprese edilmektedir. Bu durum, damar geriminde karşıt etkilere aracılık etmesi nedeni ile önemlidir. Apelin, fizyolojik koşullarda genellikle endotelyal nitrik oksit sentaz/nitrik oksit (NO) yolağının aktivasyonu aracılığıyla vazodilatatör etki gösterir. Buna karşın apelin, fonksiyonel bir endotelin olmadığı durumlarda vazokonstriksiyona neden olmaktadır. Elabela da apeline benzer şekilde vazodilatatör etki gösterir fakat NO'nun, elabelanın vazodilatatör etkisinde hiçbir rolü olmadığı düşünülmektedir. Apelin ve elabela, periferik olarak uygulandıklarında, genellikle kan basıncını düşürür ve antihipertansif etki gösterirler. Bu nedenle apelinerjik sistem, esansiyel hipertansiyon ve pulmoner hipertansiyon gibi hipertansif hastalıkların tedavisi için alternatif ajanlar geliştirme konusunda büyük bir potansiyele sahiptir. Apelin ve elabelanın yarılanma ömürleri oldukça kısadır ve güncel çalışmalar, daha uzun etkili apelinerjik analoglar geliştirmeye odaklanmıştır. Bu derlemede, apelinerjik sistemin vasküler fonksiyonel etkileri ve etki mekanizmalarına odaklandık.

Anahtar Kelimeler: Apelin; vazodilatasyon; vazokonstriksiyon; hipertansiyon; elabela
REFERENCES:
  1. Reaux A, De Mota N, Skultetyova I, Lenkei Z, El Messari S, Gallatz K, et al. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem. 2001;77(4):1085-96. [Crossref] [PubMed] 
  2. Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, et al. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept. 2001;99(2-3):87-92. [Crossref] [PubMed] 
  3. Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, et al. The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochem Biophys Res Commun. 2002;291(5):1208-12. [Crossref] [PubMed] 
  4. O'Carroll AM, Don AL, Lolait SJ. APJ receptor mRNA expression in the rat hypothalamic paraventricular nucleus: regulation by stress and glucocorticoids. J Neuroendocrinol. 2003;15(11):1095-101. [Crossref] [PubMed] 
  5. Szokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002;91(5):434-40. [Crossref] [PubMed] 
  6. Zhang L, Takara K, Yamakawa D, Kidoya H, Takakura N. Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy. Cancer Sci. 2016;107(1):36-44. [Crossref] [PubMed] [PMC] 
  7. Bertrand C, Valet P, Castan-Laurell I. Apelin and energy metabolism. Front Physiol. 2015;6:115. [Crossref] [PubMed] [PMC] 
  8. Lv SY, Yang YJ, Qin YJ, Mo JR, Wang NB, Wang YJ, et al. Central apelin-13 inhibits food intake via the CRF receptor in mice. Peptides. 2012;33(1):132-8. [Crossref] [PubMed] 
  9. Gunes I, Kartal H, Dursun AD, Sungu N, Polat YS, Erkent FD, et al. Effects of apelin-13 on myocardial ischemia reperfusion injury in streptozotocine induced diabetic rats. Bratisl Lek Listy. 2018;119(6):348-54. [Crossref]  [PubMed] 
  10. Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, et al. Characterization of apelin, the ligand for the APJ receptor. J Neurochem. 2000;74(1):34-41. [PubMed] 
  11. Japp AG, Cruden NL, Amer DA, Li VK, Goudie EB, Johnston NR, et al. Vascular effects of apelin in vivo in man. J Am Coll Cardiol. 2008;52(11):908-13. [Crossref] [PubMed] 
  12. Ishida J, Hashimoto T, Hashimoto Y, Nishiwaki S, Iguchi T, Harada S, et al. Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J Biol Chem. 2004;279(25):26274-9. [Crossref] [PubMed] 
  13. O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene. 1993;136(1-2):355-60. [PubMed] 
  14. Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, et al. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem. 2000;275(28):21061-7. [Crossref] [PubMed] 
  15. Xu J, Chen L, Jiang Z, Li L. Biological functions of Elabela, a novel endogenous ligand of APJ receptor. J Cell Physiol. 2018;233(9):6472-82. [Crossref] [PubMed] 
  16. Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther. 2005;107(2):198-211. [Crossref] [PubMed] 
  17. Zhang Y, Wang Y, Lou Y, Luo M, Lu Y, Li Z, et al. Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin. Peptides. 2018;109:23-32. [Crossref] [PubMed] 
  18. Jia YX, Lu ZF, Zhang J, Pan CS, Yang JH, Zhao J, et al. Apelin activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides. 2007;28(10):2023-9. [Crossref] [PubMed] 
  19. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun. 1998;251(2):471-6. [Crossref]  [PubMed] 
  20. Zhen EY, Higgs RE, Gutierrez JA. Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Anal Biochem. 2013;442(1):1-9. [Crossref] [PubMed] 
  21. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension. 2009;54(3):598-604. [Crossref] [PubMed] 
  22. Huang Z, Luo X, Liu M, Chen L. Function and regulation of apelin/APJ system in digestive physiology and pathology. J Cell Physiol. 2019;234(6):7796-810. [Crossref] [PubMed] 
  23. Wysocka MB, Pietraszek-Gremplewicz K, Nowak D. The role of apelin in cardiovascular diseases, obesity and cancer. Front Physiol. 2018;9:557. [Crossref] [PubMed] [PMC] 
  24. Yang P, Read C, Kuc RE, Buonincontri G, Southwood M, Torella R, et al. Elabela/toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension. Circulation. 2017;135(12):1160-73. [Crossref] [PubMed] [PMC] 
  25. Japp AG, Cruden NL, Barnes G, van Gemeren N, Mathews J, Adamson J, et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation. 2010;121(16):1818-27. [Crossref]  [PubMed] 
  26. Barnes GD, Alam S, Carter G, Pedersen CM, Lee KM, Hubbard TJ, et al. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail. 2013;6(3):482-91. [PubMed] 
  27. Shin K, Kenward C, Rainey JK. Apelinergic system structure and function. Compr Physiol. 2017;8(1):407-50. [Crossref] [PubMed] [PMC] 
  28. Yamaleyeva LM, Shaltout HA, Varagic J. Apelin-13 in blood pressure regulation and cardiovascular disease. Curr Opin Nephrol Hypertens. 2016;25(5):396-403. [Crossref] [PubMed] 
  29. Gurzu B, Petrescu BC, Costuleanu M, Petrescu G. Interactions between apelin and angiotensin II on rat portal vein. J Renin Angiotensin Aldosterone Syst. 2006;7(4):212-6. [Crossref] [PubMed] 
  30. Salcedo A, Garijo J, Monge L, Fernández N, Luis García-Villalón A, Sánchez Turrión V, et al. Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids. Regul Pept. 2007;144(1-3):50-5. [Crossref] [PubMed] 
  31. Andersen CU, Markvardsen LH, Hilberg O, Simonsen U. Pulmonary apelin levels and effects in rats with hypoxic pulmonary hypertension. Respir Med. 2009;103(11):1663-71. [Crossref] [PubMed] 
  32. Huang P, Fan XF, Pan LX, Gao YQ, Mao SZ, Hu LG, et al. [Effect of apelin on vasodilatation of isolated pulmonary arteries in rats is concerned with the nitric oxide pathway]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2011;27(1):1-5. [PubMed] 
  33. Wang Z, Yu D, Wang M, Wang Q, Kouznetsova J, Yang R, et al. Elabela-apelin receptor signaling pathway is functional in mammalian systems. Sci Rep. 2015;5:8170. [Crossref] [PubMed] [PMC] 
  34. Mughal A, Sun C, O'Rourke ST. Activation of large conductance, calcium-activated potassium channels by nitric oxide mediates apelin-induced relaxation of isolated rat coronary arteries. J Pharmacol Exp Ther. 2018;366(2):265-73. [Crossref] [PubMed] [PMC] 
  35. Zhong JC, Yu XY, Huang Y, Yung LM, Lau CW, Lin SG. Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res. 2007;74(3):388-95. [Crossref] [PubMed] 
  36. Japp AG, Newby DE. The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochem Pharmacol. 2008;75(10):1882-92. [Crossref] [PubMed] 
  37. Rastaldo R, Cappello S, Folino A, Losano G. Effect of apelin-apelin receptor system in postischaemic myocardial protection: a pharmacological postconditioning tool? Antioxid Redox Signal. 2011;14(5):909-22. [Crossref] [PubMed] 
  38. Ladeiras-Lopes R, Ferreira-Martins J, Leite-Moreira AF. The apelinergic system: the role played in human physiology and pathology and potential therapeutic applications. Arq Bras Cardiol. 2008;90(5):343-9. [Crossref] [PubMed] 
  39. Modgil A, Guo L, O'Rourke ST, Sun C. Apelin-13 inhibits large-conductance Ca2+-activated K+ channels in cerebral artery smooth muscle cells via a PI3-kinase dependent mechanism. PLoS One. 2013;8(12):e83051. [Crossref] [PubMed] [PMC] 
  40. Katugampola SD, Maguire JJ, Matthewson SR, Davenport AP. [(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man. Br J Pharmacol. 2001;132(6):1255-60. [Crossref] [PubMed] [PMC] 
  41. Pitkin SL, Maguire JJ, Kuc RE, Davenport AP. Modulation of the apelin/APJ system in heart failure and atherosclerosis in man. Br J Pharmacol. 2010;160(7):1785-95. [Crossref] [PubMed] [PMC] 
  42. Wang LY, Zhang DL, Zheng JF, Zhang Y, Zhang QD, Liu WH. Apelin-13 passes through the ADMA-damaged endothelial barrier and acts on vascular smooth muscle cells. Peptides. 2011;32(12):2436-43. [Crossref] [PubMed] 
  43. Hashimoto T, Kihara M, Ishida J, Imai N, Yoshida S, Toya Y, et al. Apelin stimulates myosin light chain phosphorylation in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2006;26(6):1267-72. [Crossref] [PubMed] 
  44. Mughal A, Sun C, OʼRourke ST. Apelin reduces nitric oxide-ınduced relaxation of cerebral arteries by ınhibiting activation of large-conductance, calcium-activated K channels. J Cardiovasc Pharmacol. 2018;71(4):223-32. [Crossref] [PubMed] [PMC] 
  45. Lee DK, Saldivia VR, Nguyen T, Cheng R, George SR, O'Dowd BF. Modification of the terminal residue of apelin-13 antagonizes its hypotensive action. Endocrinology. 2005;146(1):231-6. [PubMed] 
  46. Cheng X, Cheng XS, Pang CC. Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats. Eur J Pharmacol. 2003;470(3):171-5. [Crossref] [PubMed] 
  47. Najafipour H, Soltani Hekmat A, Nekooian AA, Esmaeili-Mahani S. Apelin receptor expression in ischemic and non- ischemic kidneys and cardiovascular responses to apelin in chronic two-kidney-one-clip hypertension in rats. Regul Pept. 2012;178(1-3):43-50. [Crossref] [PubMed] 
  48. Charles CJ, Rademaker MT, Richards AM. Apelin-13 induces a biphasic haemodynamic response and hormonal activation in normal conscious sheep. J Endocrinol. 200;189(3):701-10. [Crossref] [PubMed] 
  49. Kagiyama S, Fukuhara M, Matsumura K, Lin Y, Fujii K, Iida M. Central and peripheral cardiovascular actions of apelin in conscious rats. Regul Pept. 2005;125(1-3):55-9. [Crossref] [PubMed] 
  50. Han X, Zhang DL, Yin DX, Zhang QD, Liu WH. Apelin-13 deteriorates hypertension in rats after damage of the vascular endothelium by ADMA. Can J Physiol Pharmacol. 2013;91(9):708-14. [Crossref] [PubMed] 
  51. Nagano K, Ishida J, Unno M, Matsukura T, Fukamizu A. Apelin elevates blood pressure in ICR mice with L NAME induced endothelial dysfunction. Mol Med Rep. 2013;7(5):1371-5. [Crossref] [PubMed] [PMC] 
  52. Zhang F, Sun HJ, Xiong XQ, Chen Q, Li YH, Kang YM, et al. Apelin-13 and APJ in paraventricular nucleus contribute to hypertension via sympathetic activation and vasopressin release in spontaneously hypertensive rats. Acta Physiol (Oxf). 2014;212(1):17-27. [Crossref] [PubMed] 
  53. Zhang Q, Yao F, Raizada MK, O'Rourke ST, Sun C. Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circ Res. 2009;104(12):1421-8. [Crossref] [PubMed] [PMC] 
  54. Seyedabadi M, Goodchild AK, Pilowsky PM. Site-specific effects of apelin-13 in the rat medulla oblongata on arterial pressure and respiration. Auton Neurosci. 2002;101(1-2):32-8. [Crossref] [PubMed] 
  55. Yao F, Modgil A, Zhang Q, Pingili A, Singh N, O'Rourke ST, et al. Pressor effect of apelin-13 in the rostral ventrolateral medulla: role of NAD(P)H oxidase-derived superoxide. J Pharmacol Exp Ther. 2011;336(2):372-80. [Crossref] [PubMed] [PMC] 
  56. Cudnoch-Jedrzejewska A, Gomolka R, Szczepanska-Sadowska E, Czarzasta K, Wrzesien R, Koperski L, et al. High-fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats. Clin Exp Pharmacol Physiol. 2015;42(1):52-62. [Crossref] [PubMed] 
  57. Dai T, Ramirez-Correa G, Gao WD. Apelin increases contractility in failing cardiac muscle. Eur J Pharmacol. 2006;553(1-3):222-8. [Crossref] [PubMed] [PMC] 
  58. Zhong JC, Yu XY, Huang Y, Yung LM, Lau CW, Lin SG. Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res. 2007;74(3):388-95. [Crossref] [PubMed] 
  59. Zhong JC, Huang Y, Yung LM, Lau CW, Leung FP, Wong WT, et al. The novel peptide apelin regulates intrarenal artery tone in diabetic mice. Regul Pept. 2007;144(1-3):109-14. [Crossref] [PubMed] 
  60. Andersen CU, Hilberg O, Mellemkjær S, Nielsen-Kudsk JE, Simonsen U. Apelin and pulmonary hypertension. Pulm Circ. 2011;1(3):334-46. [Crossref] [PubMed] [PMC] 
  61. Brame AL, Maguire JJ, Yang P, Dyson A, Torella R, Cheriyan J, et al. Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension. 2015;65(4):834-40. [Crossref] [PubMed] [PMC] 
  62. Iturrioz X, Alvear-Perez R, De Mota N, Franchet C, Guillier F, Leroux V, et al. Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J. 2010;24(5):1506-17. [Crossref] [PubMed] 
  63. Gerbier R, Alvear-Perez R, Margathe JF, Flahault A, Couvineau P, Gao J, et al. Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects. FASEB J. 2017;31(2):687-700. [Crossref] [PubMed] 
  64. Chng SC, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27(6):672-80. [Crossref] [PubMed] 
  65. Pauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, et al. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science. 2014;343(6172):1248636. [Crossref] [PubMed] [PMC] 
  66. Perjés Á, Kilpiö T, Ulvila J, Magga J, Alakoski T, Szabó Z, et al. Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. Basic Res Cardiol. 2016;111(1):2. [PubMed] 
  67. Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, et al. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage. Cardiovasc Res. 2017;113(7):760-9. [Crossref] [PubMed] 
  68. Chun HJ, Ali ZA, Kojima Y, Kundu RK, Sheikh AY, Agrawal R, et al. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J Clin Invest. 2008;118(10):3343-54. [PubMed] [PMC] 
  69. Murza A, Sainsily X, Coquerel D, Côté J, Marx P, Besserer-Offroy É, et al. Discovery and structure-activity relationship of a bioactive fragment of ELABELA that modulates vascular and cardiac functions. J Med Chem. 2016;59(7):2962-72. [Crossref] [PubMed] 
  70. Ho L, van Dijk M, Chye STJ, Messerschmidt DM, Chng SC, Ong S, et al. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science. 2017;357(6352):707-13. [Crossref] [PubMed] 
  71. Li Y, Yang X, Ouyang S, He J, Yu B, Lin X, et al. Declined circulating Elabela levels in patients with essential hypertension and its association with impaired vascular function: a preliminary study. Clin Exp Hypertens. 2020;42(3):239-43. [Crossref] [PubMed] 

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4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com