Kan Akımının Yerel Olarak Düzenlenmesinde Eritrositlerin Rolü

Öz

Amaç: Eritrositler basit yapılarından dolayı son yıllara kadar, fonksiyonları solunum gazlarının taşınmasıyla çevrelenmiş hücreler olarak değerlendirilmiştir. Oysa günümüzde, eritrositlerin bir çok hücre içi sinyal yolağına sahip olduğu ve dolaşım sisteminde hücrelerin karşılaştıkları mekanik kuvvetlerin etkisinde bu yolakların bir kısmının aktive olduğu bilinmektedir. Aktive olan bu yolaklar sonucu açığa çıkan bazı vazoaktif ürünlerin ise dolaşımın yerel düzenlenmesinde rolü olabileceği gösterilmiştir. Gereç ve Yöntemler: Derleme makalemizde eritrositlerden farklı koşullarda salgılanan vazoaktif ajanların yerel kan akımını düzenlenmesinde rol aldığını gösteren çalışmalarımızın ayrıntıları yer almaktadır. Bulgular: Çalışmalarımızın sonuçları, eritrosit nitrik oksit sentaz NOS enziminin hücrelerin maruz kaldığı mekanik kuvvetlerin etkisiyle aktifleştiğini, hücrelerde nitrik oksit NO üretiminin arttığını ve bu NO’nun hücre dışına çıkarak damar düz kasında anlamlı bir gevşeme yanıtına neden olduğu ilk kez gösterilmiştir.Sonuç: Eritrositler vazoaktif ajanlar salgılayarak dolaşımın yerel düzenlenmesinde rol almaktadır

Anahtar Kelimeler

• Eritrosit, Yerel kan akımı, NOS

Role of Erythrocytes on Local Blood Flow Regulation

Öz

Objective: Erythrocytes are known as carriers of respiratory gasses, due to their simple structure. However, it is well known that erythrocytes have many intracellular signalling mechanisms that can be activated in response to mechanical forces. The vasoactive substances released from red blood cells as a result of these activated mechanisms have been shown to be effective in the regulation of local circulation. Material and Methods: In this review article, we present a summary of our research results demonstrating the effects of vasoactive substances released from erythrocytes under different conditions. Results: The results of our studies demonstrated for the first time that erythrocyte nitric oxide synthase NOS enzyme is activated by mechanical forces and nitric oxide NO production is increased in erythrocytes. This NO then diffuses to smooth muscle cells where it causes relaxation. Conclusion: Erythrocytes play a role in local blood flow regulation by releasing vasoactive substances

Anahtar Kelimeler

• Erythrocyte, Local blood flow , Set back, NOS

Kaynakça

1. 1. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. Am J Physiol 1995; 269(6 Pt 2): H2155-61.
2. 2. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9(12): 1498-505.
3. 3. Jia L, Bonaventura C, Bonaventura J, Stamler JS. S-nitrosohaemoglobin: A dynamic activity of blood involved in vascular control. Nature 1996; 380(6571): 221-6.
4. 4. Barvitenko NN, Adragna NC, Weber RE. Erythrocyte signal transduction pathways, their oxygenation dependence and functional significance. Cell Physiol Biochem 2005; 15(1-4): 1-18.
5. 5. Datta B, Tufnell-Barrett T, Bleasdale RA, Jones CJ, Beeton I, Paul V, Frenneaux M, James P. Red blood cell nitric oxide as an endocrine vasoregulator: A potential role in congestive heart failure. Circulation 2004; 109(11): 1339-42.
6. 6. Gladwin MT, Crawford JH, Patel RP. The biochemistry of nitric oxide, nitrite, and hemoglobin: Role in blood flow regulation. Free Radic Biol Med 2004; 36(6): 707-17.
7. 7. Diesen DL, Hess DT, Stamler JS. Hypoxic vasodilation by red blood cells: Evidence for an s-nitrosothiol-based signal. Circ Res 2008; 103(5): 545-53.
8. 8. Sprague RS, Hanson MS, Achilleus D, Bowles EA, Stephenson AH, Sridharan M, Adderley S, Procknow J, Ellsworth ML. Rabbit erythrocytes release ATP and dilate skeletal muscle arterioles in the presence of reduced oxygen tension. Pharmacol Rep 2009; 61(1): 183-90.

9. 9. Miseta A, Bogner P, Berényi E, Kellermayer M, Galambos C, Wheatley DN, Cameron IL. Relationship between cellular ATP, potassium, sodium and magnesium concentrations in mammalian and avian erythrocytes. Biochim Biophys Acta 1993; 1175(2): 133-9.
10. 10. Bergfeld GR, Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res 1992; 26(1): 40-7.
11. 11. You J, Johnson TD, Childres WF, Bryan RM Jr. Endothelial-mediated dilations of rat middle cerebral arteries by ATP and ADP. Am J Physiol 1997; 273(3 Pt 2): H1472-7.
12. 12. Sprague RS, Ellsworth ML, Stephenson AH, Lonigro AJ. ATP: The red blood cell link to NO and local control of the pulmonary circulation. Am J Physiol 1996; 271(6 Pt 2): H2717-22.
13. 13. Sprague RS, Ellsworth ML, Stephenson AH, Kleinhenz ME, Lonigro AJ. Deformation-induced ATP release from red blood cells requires CFTR activity. Am J Physiol 1998; 275(5 Pt 2): H1726-32.
14. 14. Sprague RS, Stephenson AH, Bowles EA, Stumpf MS, Lonigro AJ. Reduced expression of G(i) in erythrocytes of humans with type 2 diabetes is associated with impairment of both cAMP generation and ATP release. Diabetes 2006; 55(12): 3588-93.
15. 15. Ellsworth ML. The red blood cell as an oxygen sensor: What is the evidence? Acta Physiol Scand 2000; 168(4): 551-9.
16. 16. Jagger JE, Bateman RM, Ellsworth ML, Ellis CG. Role of erythrocyte in regulating local O2 delivery mediated by hemoglobin oxygenation. Am J Physiol Heart Circ Physiol 2001; 280(6): H2833-9.
17. 17. Olearczyk JJ, Stephenson AH, Lonigro AJ, Sprague RS. Receptor-mediated activation of the heterotrimeric G-protein Gs results in ATP release from erythrocytes. Med Sci Monit 2001; 7(4): 669-74.
18. 18. Han TH, Hyduke DR, Vaughn MW, Fukuto JM, Liao JC. Nitric oxide reaction with red blood cells and hemoglobin under heterogeneous conditions. Proc Natl Acad Sci USA 2002; 99(11): 7763-8.
19. 19. Vaughn MW, Kuo L, Liao JC. Effective diffusion distance of nitric oxide in the microcirculation. Am J Physiol 1998; 274(5 Pt 2): H1705-14.
20. 20. Liao JC, Hein TW, Vaughn MW, Huang KT, Kuo L. Intravascular flow decreases erythrocyte consumption of nitric oxide. Proc Natl Acad Sci USA 1999; 96(15): 8757- 61.
21. 21. Stamler JS, Jia L, Eu JP, McMahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997; 276(5321): 2034-7.
22. 22. Azarov I, Huang KT, Basu S, Gladwin MT, Hogg N, Kim-Shapiro DB. Nitric oxide scavenging by red blood cells as a function of hematocrit and oxygenation. J Biol Chem 2005; 280(47): 39024-32.
23. 23. Rifkind JM, Nagababu E, Cao Z, Barbiro-Michaely E, Mayevsky A. Nitrite-induced improved blood circulation associated with an increase in a pool of RBC-NO with no bioactivity. Adv Exp Med Biol 2009; 645: 27-34.
24. 24. Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax T, Kumara I, Gharini P, Kabanova S, Ozüyaman B, Schnürch HG, Gödecke A, Weber AA, Robenek M, Robenek H, Bloch W, Rösen P, Kelm M. Red blood cells express a functional endothelial nitric oxide synthase. Blood 2006; 107(7): 2943-51.
25. 25. Ulker P, Sati L, Celik-Ozenci C, Meiselman HJ, Baskurt OK. Mechanical stimulation of nitric oxide synthesizing mechanisms in erythrocytes. Biorheology 2009; 46(2): 121-32.
26. 26. Barry W, Allen JSS, Clude A. Piantadosi, Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation. Trends in molecular medicine 2009. Article in press.
27. 27. Allen BW, Piantadosi CA. How do red blood cells cause hypoxic vasodilation? The SNO-hemoglobin paradigm. Am J Physiol Heart Circ Physiol 2006; 291(4): H1507-12.
28. 28. Myers PR, Minor RL Jr, Guerra R Jr, Bates JN, Harrison DG. Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide. Nature 1990; 345(6271): 161-3.
29. 29. Dufour SP, Patel RP, Brandon A, Teng X, Pearson J, Barker H, Ali L, Yuen AH, Smolenski RT, GonzálezAlonso J. Erythrocyte-dependent regulation of human skeletal muscle blood flow: Role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP. Am J Physiol Heart Circ Physiol 2010; 299(6): H1936-46.
30. 30. Doyle MP, Pickering RA, DeWeert TM, Hoekstra JW, Pater D. Kinetics and mechanism of the oxidation of human deoxyhemoglobin by nitrites. J Biol Chem 1981; 256(23): 12393-8.
31. 31. Hunter CJ, Dejam A, Blood AB, Shields H, KimShapiro DB, Machado RF, Tarekegn S, Mulla N, Hopper AO, Schechter AN, Power GG, Gladwin MT. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 2004; 10(10): 1122-7.
32. 32. Rhodes P, Leone AM, Francis PL, Struthers AD, Moncada S, Rhodes P. The L-arginine: Nitric oxide pathway is the major source of plasma nitrite in fasted humans. Biochem Biophys Res Commun 1995; 209(2): 590-6.
33. 33. Gödecke A, Decking UK, Ding Z, Hirchenhain J, Bidmon HJ, Gödecke S, Schrader J. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ Res 1998;82(2): 186-94.
34. 34. Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O, Scheeren T, Gödecke A, Schrader J, Schulz R, Heusch G, Schaub GA, Bryan NS, Feelisch M, Kelm M. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 2003; 35(7): 790-6.
35. 35. Meulemans A, Delsenne F. Measurement of nitrite and nitrate levels in biological samples by capillary electrophoresis. J Chromatogr B Biomed Appl 1994; 660(2): 401-4.
36. 36. Gorenflo M, Zheng C, Pöge A, Bettendorf M, Werle E, Fiehn W, Ulmer HE. Metabolites of the L-arginine-NO pathway in patients with left-to-right shunt. Clin Lab 2001; 47(9-10): 441-7.
37. 37. Dejam A, Hunter CJ, Pelletier MM, Hsu LL, Machado RF, Shiva S, Power GG, Kelm M, Gladwin MT, Schechter AN. Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 2005; 106(2): 734-9.
38. 38. Jensen FB. Nitrite disrupts multiple physiological functions in aquatic animals. Comp Biochem Physiol A Mol Integr Physiol 2003; 135(1): 9-24.
39. 39. May JM, Qu ZC, Xia L, Cobb CE. Nitrite uptake and metabolism and oxidant stress in human erythrocytes. Am J Physiol Cell Physiol 2000; 279(6): C1946-54.
40. 40. Webb AJ, Milsom AB, Rathod KS, Chu WL, Qureshi S, Lovell MJ, Lecomte FM, Perrett D, Raimondo C, Khoshbin E, Ahmed Z, Uppal R, Benjamin N, Hobbs AJ, Ahluwalia A. Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase. Circ Res 2008; 103(9): 957-64.
41. 41. Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Hogg N, Schechter AN, Gladwin MT. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 2005; 115(8): 2099-107.
42. 42. Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD Jr, Kraus D, Ho C, Gladwin MT, Patel RP. Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 2006; 107(2): 566-74.
43. 43. Ignarro LJ, Gruetter CA. Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite: Possible involvement of S-nitrosothiols. Biochim Biophys Acta 1980; 631(2): 221-31.
44. 44. Moulds RF, Jauernig RA, Shaw J. A comparison of the effects of hydrallazine, diazoxide, sodium nitrite and sodium nitroprusside on human isolated arteries and veins. Br J Clin Pharmacol 1981; 11(1): 57-61.
45. 45. Lancaster JR Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci USA 1994; 91(17): 8137-41.
46. 46. Buerk DG. Nitric oxide regulation of microvascular oxygen. Antioxid Redox Signal 2007; 9(7): 829-43.
47. 47. Chen K, Piknova B, Pittman RN, Schechter AN, Popel AS. Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes. Nitric Oxide 2008; 18(1): 47- 60.
48. 48. Moncada S. Nitric oxide in the vasculature: Physiology and pathophysiology. Ann N Y Acad Sci 1997; 811: 60-7; discussion 67-9.
49. 49. Kang ES, Ford K, Grokulsky G, Wang YB, Chiang TM, Acchiardo SR. Normal circulating adult human red blood cells contain inactive NOS proteins. J Lab Clin Med 2000; 135(6): 444-51.
50. 50. Bratosin D, Estaquier J, Petit F, Arnoult D, Quatannens B, Tissier JP, Slomianny C, Sartiaux C, Alonso C, Huart JJ, Montreuil J, Ameisen JC. Programmed cell death in mature erythrocytes: A model for investigating death effector pathways operating in the absence of mitochondria. Cell Death Differ 2001; 8(12): 1143-56.
51. 51. Ozüyaman B, Grau M, Kelm M, Merx MW, Kleinbongard P. RBC NOS: Regulatory mechanisms and therapeutic aspects. Trends Mol Med 2008; 14(7): 314-22.
52. 52. Carvalho FA, Mesquita R, Martins-Silva J, Saldanha C. Acetylcholine and choline effects on erythrocyte nitrite and nitrate levels. J Appl Toxicol 2004; 24(6): 419-27.
53. 53. Fischer UM, Schindler R, Brixius K, Mehlhorn U, Bloch W. Extracorporeal circulation activates endothelial nitric oxide synthase in erythrocytes. Ann Thorac Surg 2007; 84(6): 2000-3.
54. 54. Ulker P, Yaras N, Yalcin O, Celik-Ozenci C, Johnson PC, Meiselman HJ, Baskurt OK. Shear stress activation of nitric oxide synthase and increased nitric oxide levels in human red blood cells. Nitric Oxide 2011; 24(4): 184-91.
55. 55. Ulker P, Meiselman HJ, Baskurt OK. Nitric oxide generation in red blood cells induced by mechanical stress. Clin Hemorheol Microcirc 2010; 45(2-4): 169-75.
56. 56. Ulker P, Gunduz F, Meiselman HJ, Baskurt OK. Nitric oxide generated by red blood cells following exposure to shear stress dilates isolated small mesenteric arteries under hypoxic conditions. Clin Hemorheol Microcirc 2013; 54(4): 357-69.