ERİTROPOETİN VE KARDİYOVASKÜLER SİSTEM

Yıl 2012, Cilt: 1 Sayı: 3, 148 - 153, 31.12.2012

Aysel Güven Bağla Meltem İçkin

Öz

Eritropoetin (EPO), sağlıklı bireylerde kemik iliğinde normal eritrosit üretimi için gerekli olan bir glikoprotein hormondur. Hipoksik koşullar altında eritropoezi indükler. Renal peritübüler hücrelerden ve karaciğer, dalak, akciğer, beyin, kemik iliği, üreme organları gibi farklı ekstrarenal dokulardan salınır. EPO ile reseptörünün (EPO-R) etkileşimi, eritroid progenitör hücrelerin programlanmış hücre ölümünü (apopitozis) azaltır ve bu hücrelerin kemik iliğinde farklılaşmasını teşvik eder. Klinik olarak, rHuEPO (rekombinant insan EPO) kronik böbrek yetmezliği sonucu gelişen EPO eksikliğine bağlı anemi tedavisinde 1980'lerin sonlarından beri kullanılmaktadır. EPO-R, eritroid progenitor hücrelerin yanı sıra, nöronlar, endotel hücreleri, vasküler düz kas hücreleri ve kalp kası hücreleri gibi çeşitli hücre gruplarında da eksprese edilir. EPO nun kalp, böbrekler, retina, karaciğer, akciğer, bağırsaklar ve beyinde hipoksi ve iskemi-reperfüzyon hasarına karşı sitoprotektif etkiye sahip olduğu gösterilmiştir. EPO’nun temel sitoprotektif etkisinin iskemik/hipoksik dokuda apopitozisi inhibe etmek olduğu öne sürülmüştür. Apopitozisin inhibisyonu yanı sıra, EPO doğrudan ya da dolaylı olarak hücreleri koruyan pek çok farklı etki de göstermektedir. Bu nedenle EPO genel doku koruyucu bir sitokin olarak değerlendirilmelidir.

Anahtar Kelimeler

Eritropoetin, kök hücre

ERYTHROPOIETIN AND CARDIOVASCULAR SYSTEM

Öz

Erythropoietin (EPO) is a glycoprotein hormone which is essential for normal erythrocyte production in bone marrow in healthy subjects. It induces erythropoiesis under hypoxic conditions. It is released from renal peritubular cells and various extrarenal tissues like liver, spleen, brain, lungs, bone marrow, reproductive organs. Interaction of EPO with its receptor (EPO-R) decreases programmed death (apoptosis) of erythroid progenitor cells and promotes their differentiation in bone marrow. Clinically, rHuEPO (recombinant human EPO) has been used since the late 1980s in patients with anaemia due to EPO deficiency as a consequence of chronic renal failure. In addition to erythroid progenitor cells, a varied group of cells including neurons, endothelial cells, vascular smooth muscle cells, and cardiac myocytes express EPO-R. It has been shown that Epo has cytoprotective properties against ischemia reperfusion damage and hypoxia in the brain, heart, kidneys, retina, liver, lungs, and intestines. It was suggested that inhibition of apoptosis in ischemic/hypoxic tissue is the major cytoprotective effect of EPO. In addition to inhibition of apoptosis, EPO exhibits many other actions that serve to protect cells either directly or indirectly. EPO should therefore be regarded also as a general tissueprotective cytokine.

Anahtar Kelimeler

Erythropoietin, stem cell

Kaynakça

• 1. Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev 1992 72: 449–489,
• 2. Eckardt KU, Koury ST, Tan CC, et al. Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia. Kidney Int. 1993 Apr;43(4):815-23.
• 3. Fisher JW. Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 2003 Jan;228(1):1-14.
• 4. Wenger RH. Mammalian oxygen sensing, signalling and gene regulation. J Exp Biol. 2000;203:1253-63. 6.
• 5. Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci USA. 1993;90:2423-7.
• 6. Jelkmann W. Molecular biology of erythropoietin. Intern Med. 2004;43:649–59.
• 7. Jie KE, Verhaar MC, Cramer MJ, et al. Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors. Am J Physiol Renal Physiol. 2006 Nov;291(5):F932-44.
• 8. Kishore BK, Isaac J, Westenfelder C. Administration of poly-D-glutamic acid induces proliferation of erythropoietin-producing peritubular cells in rat kidney. Am J Physiol Renal Physiol. 2007 Feb;292(2):F749-61.
• 9. Maxwell AP, Lappin TR, Johnston CF, Bridges JM, McGeown MG. Erythropoietin production in kidney tubular cells. Br J Haematol. 1990 Apr;74(4):535-9.
• 10. Ebert BL and Bunn HF. Regulation of the erythropoietin gene. Blood94: 1864–1877, 1999
• 11. Palis J, Malik J, McGrath KE, Kingsley PD. Primitive erythropoiesis in the mammalian embryo. Int J Dev Biol. 2010;54(6-7):1011-8. Review.
• 12. Kessinger A and Sharp G. Mobilization of hematopoietic progenitor cells with epoetin alfa. Semin Hematol 2001; 33 (Suppl.10) (Abstr.).
• 13. Kimura T, Sonoda Y, Iwai N, et al. Proliferation and cell death of embryonic primitive erythrocytes. Exp Hematol. 2000 Jun;28(6):635-41.
• 14. George J, Goldstein E, Abashidze A, et al. Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner. Cardiovasc Res. 2005 Nov 1;68(2):299-306.
• 15. van der Meer P, Voors AA, Lipsic E, van Gilst WH, van Veldhuisen DJ. Erythropoietin in cardiovascular diseases. Eur Heart J. 2004 Feb;25(4):285-91. Review
• 16. Erbayraktar S, de Lanerolle N, de Lotbinière A, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med. 2006;12:74-80.
• 17. Sirén AL and Ehrenreich H. Erythropoietin-a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci. 2001;251:179-84.
• 18. Celik M, Gokmen N, Erbayraktar S, et al. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA. 2002;99:2258–63.
• 19. Erbayraktar S, Grasso G, Sfacteria A, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA. 2003;100:6741-6.
• 20. Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci 2004;101:14907-14912
• 21. Cai Z, Manalo DJ, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 2003;108:79-85.
• 22. Cai Z and Semenza GL. Phosphatidylinositol-3-kinase signaling is required for erythropoietin-mediated acute protection against myocardial ischemia/reperfusion injury. Circulation 2004;109:2050-2053.
• 23. Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci 2003;100:4802-4806.
• 24. Guneli E, Cavdar Z, Islekel H, et al. Erythropoietin protects the intestine against ischemia/reperfusion injury in rats. Mol Med 2007;13:509-517.
• 25. Junk AK, Mammis A, Savitz SI, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci 2002;99:10659-10664.
• 26. Lipsic E, van der Meer P, Henning RH, et al. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol 2004;44:473-479.
• 27. Moon C, Krawczyk M, Ahn D, et al. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci 2003;100:11612-11617.
• 28. Parsa CJ, Matsumoto A, Kim J, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 2003;112:999-1007.
• 29. Sharples EJ, Patel N, Brown P, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 2004;15:2115-2124.
• 30. Solaroglu A, Dede FS, Okutan E, Bayrak A, Haberal A, Kilinc K. A single dose of erythropoietin attenuates lipid peroxidation in experimental liver ischemia-reperfusion injury in the rat fetus. J Matern Fetal Neonatal Med 2004;16:231-234.
• 31. Wu H, Ren B, Zhu J, et al. Pretreatment with recombined human erythropoietin attenuates ischemia-reperfusion-induced lung injury in rats. Eur J Cardiothorac Surg 2006;29:902-907.
• 32. Marzo F, Lavorgna A, Coluzzi G, et al. Erythropoietin in heart and vessels: focus on transcription and signalling pathways. J Thromb Thrombolysis 2008;26:183-187
• 33. Fiordaliso F, Chimenti S, Staszewsky L, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemiareperfusion injury. Proc Natl Acad Sci 2005;102:2046-2051.
• 34. Ueba H, Brines M, Yamin M, et al. Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin.Proc Natl Acad Sci 2010;107:14357-14362
• 35. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 2004;207:3233-3242.
• 36. Juul SE, Yachinis AT, Rojiani AM and Christensen RD. Immunohistochemical Localization of Erythropoietin and Its Receptor in the Developing Human Brain. Pediat. Dev. Pathol. 1999, 2: 148–15
• 37. Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999 Aug;126(16):3597-605