GHRELIN AS A POTENTIAL BIOMARKER AND MEDICAL DRUG

Zaychenko G. V., Gorchakova N. O., Savchenko N. V., Klymenko O. V., Sorocopud K. Ju.

LITERATURE REVIEWS

Scentific article

Cardio-vascular treatment and diagnostics is one of the main medicine problem all over the world. Although there are many drugs with proved effectivity for cardiovascular diseases treatment, the searching of the new possibilities for the better diagnostics and cure is continued. In the review it is shown physiological, pathophysiological and pharmacological ghrelin role in the function of cardiovascular system. Ghrelin is a multifunctional peptide hormone, mainly synthesized by P/D1cells of the stomach fundus mucosa. It was found in the pancreas, hypophysis, heart, kidney, lungs, placenta vessels. Its basic effect that is realized by GHS-R1-receptor in the arcuate and ventromedial nucleuses of hypothalamus is stimulation of the pituitary hormone synthesis. Ghrelin improves appetite, normalizes energy, carbohydrate, lipid metabolism, decreases cell proliferation and apoptosis. The first works were devoted to its ability for somatotropic hormone production intensification, appetite stimulation, leptin content lowering because leptine decreases the appetite. It is necessary for reproductive function. Later it was stated hat ghrelin improves memory, cognitive functions and teaching. It defences from depression and worry. Ghrelin increases dopamine- and cholinergic activity of CNS. Ghrelin has anabolic action, regulates growth and supports homeostasis. It oppresses fat utilization but causes hyperglycemia. Later it was shown that ghrelin oppresses cardiomyocetes apoptosis. Ghrelin has cardioprotective, vasodilator influence, takes part in the cardio- and systhrmic hemodynamics regulation. Ghrelin has antioxidant, antiapoptyc, anti-inflammatory, immunothropic action. It improves function and remodulation of the left heart ventricle in the case of cardiac insufficiency after injury of heart by ischemic-reperfusion mechanism. Cardioprotective ghrelin action is explained by decrease of cardiac rate, systolic pressure in the left ventricle, increase myocardial contraction and relaxation. Ghrelin inhibits the apoptosis of cardiomyocites and endothelial cells. Its vasodilator effect is connected with elevation the production of NO by stimulation of NO-synthase, lowering vasoconstrictor endothelin-1-level. Molecular mechanism of ghrelin action on vessels is consisted in signal way use. This effect is realized CHS-R-1a, phosphoinositide-3-kinase, alpha serin/treonin proteinkinase and endothelial synthetase (eNOS). Ghrelin lowers peripheral vascular resistance, stabilizers arterial pressure. It was investigated in the experiments that ghrelin decreases the symptoms of lung hypertension and defences the myocardium from arrythmyas appearance. There are some works that are shown the ghrelin effectivity as the biomarker in the cardiac insufficiency that is more exact comparately with troponine and sodium uretic peptide.

ghrelin, peptide hormone, regulatory action on cardio-vascular system, biomarker.

1. Voronkov LH, Liashenko AV, Tkach NA, Parashchenok LP. Khronichna sertseva nedostatnist yak multymorbidnyi stan. Ukr. kardiol. zhurnal. 2019;26(4):90-101. [in Ukrainian].
2. Ponikowski P, Anker SD, AlHabib KF, Cowie MR, Force TL, Hu S, et al. Heart failure: preventing disease and death worldwide: Addressing heart failure. ESC Heart Failure. 2014;1(1):4-25.
3. Mozaffarian D, Benjamin EJ, Go AS, Amett DK, Blaha MJ, Cushman M. Heart Disease and Stroke Statistics-2016 Update: A Report from the American Heart Association. Circulation. 2016;133(4):e38-360.
4. Sovarese G, Lund H. Global Public Health Burden of Heart Failure. Card. Fail. Rev. 1017;3:7-11.
5. Voronkov LH, Voitsekhovska KV, Fedkiv SV, Havrylenko TI, Koval VI. Predyktory dovhostrokovoho, klinichnoho poshuku patsiientiv z khronichnoiu sertsevoiu nedostatnistiu ta znyzhenoiu fraktsiieiu livoho shlunochka. Ukr. kardiol. zhurnal. 2019;26(5):33-42. [in Ukrainian].
6. Voronkov LH. Khronycheskaia serdechnaia nedostatochnost u patsyentov pozhyloho vozrasta. Krovoobih ta hemostaz. 2013;3-4:107-11. [in Russian].
7. Gruzdeva OV, Borodkina DA, Belik EV, Akbasheva OE, Palicheva EI, Barbarash OL. Grelin-fiziologiya i patofiziologiya: v tsentre vnimaniya serdechno-sosudistaya sistema. Kardiologiya. 2019;59(3):60-7. [in Russian].
8. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clinical chemistry. 2004;50(9):1511-25.
9. Oparyn AA, Oparyn LH, Kudriavtsev AA. Rol hrelyna v formyrovanyy komorbydnoho techenyia hastroеzofahalnoi refliuksnoi bolezny s sakharnуm dyabetom 2 typa u lyts molodoho vozrasta. Problemy bezperervnoi osvity i nauky. 2019;3:48-56. [in Russian].
10. Tereschenko IV, Kayushev PE. Grelin i ego rol v norme i patologii. Terapevticheskiy arhiv. 2013;4:98-101. [in Russian].
11. Sato T, Nakamura Y, Shiimura Y. Structure, regulation and function of ghrelin. J Biochemistry. 2011;51(2):119-28.
12. Cervone DT, Dyck DJ. Ghrelin and the regulation of peripheral tissue metabolism. The FASEB J. 2017;31(1):1084.
13. Sprynchuk NA, Bolshova OV. Vmist hrelinu v plazmi krovi ditei iz syndromom biolohichno neaktyvnoho hormonu rostu. Mizhnarodnyi endokrynolohichnyi zhurnal. 2018;14(5):442-8. [in Ukrainian].
14. Kirienkova EV, Litvinova LS, Seledtsov VI. Metabolicheskie i serdechno-sosudistyie effektyi grelina. Ozhirenie i metabolIzm. 2012;1:3-8. [in Russian].
15. Bolshova OV, Malinovska TM. Vmist hrelinu ta leptynu v plazmi krovi v ditei ta pidlitkiv z dysfunktsiieiu hipotalamusu. Mizhnarodnyi endokrynolohichnyi zhurnal. 2018;14(8):11-6. [in Ukrainian].
16. Sato T, Nakamura Y, Shimura Y. Structure regulation and function of ghrelin. Journal of Biochemistry. 2012;151:119-28.
17. Takaya K, Ariyasu H, Kanamoto N. Ghrelin strongly stimulates growth hormone release in humans. J Clinical Endocrinology & Metabolism. 2000;85(12):4908-11.
18. Volkov VP. Novyie pankreaticheskie gormonyi: grelin. Universum: meditsina i farmakologiya. 2014;12:13-4. [in Russian].
19. Sanger GJ, Furness JB. Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nature Reviews Gastroenterology & Hepatology. 2015;13(1):38-48.
20. Motta G, Allasia S, Chigo E. Ghrelin action on somatotropic and gonadotropic function in human. Prog. Mol. Biol. Transl. Sci. 2016;138:3-25.
21. Mendes-Sanches N, Ponciano-Rodrigu G, Bermegio-Martines L. Low serum level of ghrelin are associated with gallstone disease. World J. Gastroenterol. 2006;12(19):3096-100.
22. Müller TD, Nogueiras R, Andermann ML. Ghrelin. Molecular metabolism. 2015;4(6):437-60.
23. Alexander SPH, Benson HE, Faccenda E. The Concise Guide to PHARMACOLOGY 2013/14: G protein‐coupled receptors. British J Pharmacology. 2013;170(8):1676-705.
24. Lilleness BM, Frishman WH. Ghrelin and the Cardiovascular System. Cardiology in Review. 2016;24(6):288-97.
25. Khatib M, Simkhada P, Gode D. Cardioprotective effects of ghrelin in heart failure: from gut to heart. Heart Views. 2014;15(3):74-5.
26. Khatib MN, Shankar A, Kirubakaran R. Effect of ghrelin on mortality and cardiovascular outcomes in experimental rat and mice models of heart failure: a systematic review and meta-analysis. PloS One. 2015;10(5):e0126697.
27. Yang P. Commentary on the effects of ghrelin on the body weight, body composition, and cardiovascular function in experimental rat models of heart failure: A systematic review. Annals of Tropical Medicine and Public Health. 2015;8(4):81-7.
28. Mao Y, Tokudome T, Kishimoto I. Ghrelin and Blood Pressure Regulation. Current hypertension reports. 2016;18(2):1-6.
29. Zhang G, Teng X, Liu Y. Inhibition of endoplasm reticulum stress by ghrelin protects against ischemia/reperfusion injury in rat heart. Peptides. 2009;30(6):1109-16.
30. Huang CX, Yuan MJ, Huang H. Ghrelin inhibits postinfarct myocardial remodeling and improves cardiac function through anti-inflammation effect. Peptides. 2009;30:2286-91.
31. Ferens DM, Yin L, Bron R. Functional and in situ hybridization evidence that preganglionic sympathetic vasoconstrictor neurons express ghrelin receptors. Neuroscience. 2010;166:671-9.
32. Soeki T, Kishimoto I, Schwenke DO. Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol. 2008;294:H426-H432.
33. Sun M, Dawood F, Wen WH. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction. Circulation. 2004;110:3221-8.
34. Samolyuk MO, Grigoreva NYu. Otsenka endotelialnoy disfunktsii i vozmozhnosti ee korrektsii na sovremennom etape u bolnyih serdechnososudistyimi zabolevaniyami. Kardiologiya. 2019;59(3S):4-9. [in Russian].
35. Gkaliagkousi E, Gavriilaki E, Triantafyllou A, Douma S. Clinical Significance of Endothelial Dysfunction in Essential Hypertension. Current Reports. 2015;17(11):85-6.
36. Gruzdeva O, Uchasova E, Belik E. Lipid, adipokine and ghrelin levels in myocardial infarction patients with insulin resistance. BMC cardiovascular disorders. 2014;14(1):7-14.
37. Virdis A, Lerman L, Regoli F. Human ghrelin: a gastric hormone with cardiovascular properties. Current Pharmaceutical Design. 2016;22(1):52-8.
38. Wiley KE, Davenport AP. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol. 2002;136(8):1146-52.
39. Mattu HS, Randeva HS. Role of adipokines in cardiovascular disease. Journal of endocrinology. 2013;216(1):T17-T36.
40. Pemberton CJ, Tokola H, Bagi Z. Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion. Am J Physiol Heart Circ Physiol. 2004;287(4):H1522-H1529.
41. Iantorno M, Chen H, Kim J. Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab. 2007;292(3):E756-E764.
42. Xu Z, Lin S, Wu W. Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-kappaB pathways and mitochondrial protective mechanisms. Toxicology. 2008;247(2-3):133-8.
43. Lei L,Yuanjie M. Hormone treatments in congestive heart failure. J Int Med Res. 2018;46(6):2063-81.
44. Mao Y, Tokudome T, Otani K. Excessive sympathoactivation and deteriorated heart function after myocardial infarction in male ghrelin knockout mice. Endocrinology. 2013;154:1854-63.
45. Mao Y, Tokudome T, Kishimoto I. Hexarelin treatment in male ghrelin knockout mice after myocardial infarction. Endocrinology. 2013;154: 3847-54.
46. Yang C, Liu J. Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance. Peptides. 2018;99:27-35.
47. Warbrick I, Rabkin SW. Effect of the peptides Relaxin, Neuregulin, Ghrelin and Glucagon-like peptide-1, on cardiomyocyte factors involved in the molecular mechanisms leading to diastolic dysfunction and/or heart failure with preserved ejection fraction. Peptides. 2019;111:33-41.
48. Kleinz MJ, Maguire JJ, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyi ghrelin in the regulation of vascular tone in man. Cardiovascular Research. 2006;69(1):227-35.
49. Granata R, Isgaar J, Alloatti G. Cardiovascular actions of the ghrelin-gene peptides and growth hormone-releasing hormone. Experimental Biology and Medicine. 2011;236(5):505-14.
50. Nagaya N, Moriya J, Yasumura Y. Effects of ghrelin administration on left ventricular function,exercise capacity and muscle wasting in patients with chronic heart failure. Circulation. 2004;110:3674-9.
51. Beiras-Fernandez A, Kreth S, Weis F, Ledderose C, Pöttinger T, Dieguez C, et al. Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides. 2010;31(12):2222-8.
52. Van Kimmenade RRJ, Januzzi JL Jr. Emerging biomarkers in heart failure. Clin Chem. 2012;58(1):127-38.
53.  Sullivan R, Varinder KR. Dynamics of the Ghrelin/Growth Hormone Secretagogue Receptor System in the Human Heart Before and After Cardiac Transplantation. J Endocr Soc. 2019;3(4):748-62.
54. Sullivan R, McGirr R. Changes in the Cardiac GHSR1a-Ghrelin System Correlate With Myocardial Dysfunction in Diabetic Cardiomyopathy in Mice. J Endocr Soc. 2017;2(2):178-89.
55. Poher AL, Tschop MH, Moller TD. Ghrelin regulation of glucose metabolism. Peptides. 2018;100:236-42.
56. Belovol AN, Shkolnyk VV, Andreeva AA. Urovny hormona hrelyna u patsyentov s AH y razlychnymy proiavlenymy metabolycheskoho syndroma. Ukr. kardiol. zhurnal. 2011;27. [in Ukrainian].

«Bulletin of problems biology and medicine» Issue 1 (155), 2020 year, 39-44 pages, index UDK 616. 007. 21:612. 43/45. 018. 2+577:154. 365

10.29254/2077-4214-2020-1-155-39-44