Apelinergic System And Myocardial Contractility

Öz

The apelinergic system consists of APJ (apelin receptor), apelin and elabela. APJ is a G protein-coupled receptor. Apelin and elabela are endogenous ligands of APJ. APJ, apelin and elabela are widely expressed in cardiovascular tissues. The positive inotropic effect of apelin and elabela, which mediate vasodilator, cardioprotective and angiogenic effects, is quite potent. It is suggested that calcium-dependent and calcium-independent mechanisms play role in the positive inotropic effect of apelin after activation of phospholipase C. Elabela is thought to show positive inotropic effect by activating mitogen-activated protein kinase 1/2-extracellular signal-regulated kinase 1/2 pathway. Apelin, elabela, their analogues and APJ agonists may be an important alternative in the treatment of heart failure due to their potent positive inotropic effects. This review focuses on effects and effect mechanisms of the apelinergic system on myocardial function.

Anahtar Kelimeler

• apelin,elabela,myocard

Apelinerjik Sistem ve Miyokardiyal Kontraktilite

Öz

Apelinerjik sistem APJ (apelin reseptörü), apelin ve elabeladan oluşmaktadır. APJ, G protein kenetli bir reseptördür. Apelin ve elabela APJ’nin endojen ligandlarıdır. APJ, apelin ve elabela kardiyovasküler dokularda yaygın olarak eksprese edilmektedir. Vazodilatatör, kardiyoprotektif ve anjiyogenik etkilere aracılık eden apelin ve elabelanın pozitif inotropik etkisi oldukça güçlüdür. Apelinin pozitif inotropik etkisinde fosfolipaz C aktivasyonu sonrası kalsiyum bağımlı ve kalsiyum bağımsız mekanizmaların rol oynadığı ileri sürülmektedir. Elabelanın ise mitojenle aktiflenen protein kinaz 1/2-ekstraselüler sinyalle düzenlenen kinaz 1/2 yolağını aktive ederek pozitif inotropik etki gösterdiği düşünülmektedir. Apelin, elabela, bunların analogları ve APJ agonistleri güçlü pozitif inotropik etkileri nedeni ile kalp yetmezliği tedavisinde önemli bir tedavi alternatifi oluşturabilir. Bu derlemede apelinerjik sistemin miyokard fonksiyonuna etkileri ve etki mekanizmaları üzerinde durulmaktadır.

Anahtar Kelimeler

• apelin,elabela,miyokard

Kaynakça

1. Reaux A, De Mota N, Skultetyova I et al. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem 2001;77:1085–96.
2. Tatemoto K, Takayama K, Zou MX et al. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept 2001;99(2–3):87–92.
3. Taheri S, Murphy K, Cohen M 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;291:1208–12.
4. O’Carroll AM, Don AL, Lolait SJ. APJ receptor mRNA expression in the rat hypothalamic paraventricular nucleus: regulation by stress and glucocorticoids. J Neuroendocr 2003;15:1095–101.
5. Szokodi I, Tavi P, Földes G et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 2002;91(5):434–40.
6. Zhang L, Takara K, Yamakawa D et al. Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy. Cancer Sci 2016;107:36–44.
7. Wysocka MB, Pietraszek-Gremplewicz K, Nowak D. The Role of Apelin in Cardiovascular Diseases, Obesity and Cancer. Front Physiol 2018;9:557.
8. 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.

9. Shin K, Kenward C, Rainey JK. Apelinergic System Structure and Function. Compr Physiol 2017;8(1):407-50.
10. Lee DK, Cheng R, Nguyen T et al. Characterization of apelin, the ligand for the APJ receptor. J Neurochem 2000;74:34–41.
11. Japp AG, Cruden NL, Amer DA et al. Vascular effects of Apelin in vivo in man. J Am Coll Cardiol 2008;52:908–13.
12. Ishida J, Hashimoto T, Hashimoto Y 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;279:26274–9.
13. O’Dowd BF, Heiber M, Chan A 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.
14. Hosoya M, Kawamata Y, Fukusumi 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.
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.
16. Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther 2005;107:198–211.
17. Zhang Y, Wang Y, Lou Y et al. Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin. Peptides 2018;109:23-32.
18. Folino A, Montarolo PG, Samaja M, Rastaldo R. Effects of apelin on the cardiovascular system. Heart Fail Rev. 2015;20(4):505-18.
19. Tatemoto K, Hosoya M, Habata Y 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.
20. Zhen EY, Higgs RE, Gutierrez JA. Pyroglutamyl apelin13 identified as the major apelin isoform in human plasma. Anal Biochem 2013;442(1):1–9.
21. Mughal A, O'Rourke ST. Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol Ther 2018;190:139-147.
22. Antushevich H, Wójcik M. Review: Apelin in disease. Clin Chim Acta 2018;483:241-8.
23. Berry MF, Pirolli TJ, Jayasankar V et al. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 2004;110(11):II187– 93.
24. Atluri P, Morine KJ, Liao GP et al. Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression. Cell Mol Biol Lett 2007;12(1):127-38.
25. Principe A, Melgar-Lesmes P, Fernández-Varo G et al. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology 2008;48(4):1193-201.
26. 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.
27. Japp AG, Cruden NL, Barnes G et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 2010;121:1818–27.
28. Barnes GD, Alam S, Carter G 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.
29. Pang H, Han B, Yu T, Zong Z. Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart failure. Int J Mol Med 2014;34(3):756-64.
30. Perjes A, Skoumal R, Tenhunen O, Konyi A, Simon M, Horvath IG, Kerkela R, Ruskoaho H, Szokodi I. Apelin increases cardiac contractility via protein kinase C epsilon- and extracellular signal-regulated kinase-dependent mechanisms. PLoS One 2014;9(4):e93473.
31. Yang P, Kuc RE, Brame AL et al. [Pyr1]Apelin-13(1-12) Is a Biologically Active ACE2 Metabolite of the Endogenous Cardiovascular Peptide [Pyr1]Apelin-13. Front Neurosci 2017;11:92.
32. Yang P, Read C, Kuc RE 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.
33. Brame AL, Maguire JJ, Yang P et al. Design, characterization, and first-in human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension 2015;65:834–40.
34. Gerbier R, Alvear-Perez R, Margathe JF et al. Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects. FASEB J 2017;31:687–700.
35. Yang P, Maguire JJ, Davenport AP. Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends Pharmacol Sci 2015;36(9):560-7.
36. 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.
37. Perjes A, Skoumal R, Tenhunen O et al. Apelin increases cardiac contractility via protein kinase C epsilon- and extracellular signal-regulated kinase-dependent mechanisms. PLoS One 2014;9(4):e93473.
38. Wang C, Du JF, Wu F, Wang HC. Apelin decreases the SR Ca2? content but enhances the amplitude of [Ca2?]i transient and contractions during twitches in isolated rat cardiac myocytes. Am J Physiol Heart Circ Physiol 2008;294(6):H2540–6.
39. Dai T, Ramirez-Correa G, Gao WD. Apelin increases contractility in failing cardiac muscle. Eur J Pharmacol 2006;553(1–3):222–8.
40. Jia YX, Pan CS, Zhang J et al. Apelin protects myocardial injury induced by isoproterenol in rats. Regul Pept 2006;133(1-3):147-54.
41. Zeng XJ, Zhang LK, Wang HX, Lu LQ, Ma LQ, Tang CS. Apelin protects heart against ischemia/reperfusion injury in rat. Peptides 2009;30(6):1144-52.
42. Rastaldo R, Cappello S, Folino A et al. Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. Am J Physiol Heart Circ Physiol 2011;300(6):H2308-15.
43. Hekmat AS, Najafipour H, Nekooian AA, Esmaeli-Mahani S, Javanmardi K. Cardiovascular responses to apelin in two-kidney-one-clip hypertensive rats and its receptor expression in ischemic and non-ischemic kidneys. Regul Pept 2011;172(1-3):62-8.
44. Najafipour H, Soltani HA, 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;178:43–50.
45. Wang M, Gupta RC, Rastogi S et al. Effects of acute intravenous infusion of apelin on left ventricular function in dogs with advanced heart failure. J Card Fail 2013;19(7):509-16.
46. Zhang BH, Guo CX, Wang HX et al. Cardioprotective effects of adipokine apelin on myocardial infarction. Heart Vessels 2014;29(5):679-89.
47. Azizi Y, Faghihi M, Imani A et al. Post-infarct treatment with [Pyr(1)]apelin-13 improves myocardial function by increasing neovascularization and overexpression of angiogenic growth factors in rats. Eur J Pharmacol 2015;761:101-8.
48. Chung WJ, Cho A, Byun K et al. Apelin-13 infusion salvages the peri-infarct region to preserve cardiac function after severe myocardial injury. Int J Cardiol 2016;222:361-7.
49. 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.
50. Pauli A, Norris ML, Valen E et al. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science 2014;343:1248636.
51. Perjés Á, Kilpiö T, Ulvila J et al. Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. Basic Res Cardiol 2016;111:2.
52. Kuba K, Sato T, Imai Y, Yamaguchi T. Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. Peptides 2019;111:62-70.
53. Wang Z, Yu D, Wang M et al. Elabela-apelin receptor signaling pathway is functional in mammalian systems Sci Rep 2015;5:8170.
54. Sato T, Sato C, Kadowaki A et al. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage. Cardiovasc Res 2017;113(7):760-9.
55. Murza A, Sainsily X, Coquerel D et al. Discovery and structure-activity relationship of a bioactive fragment of ELABELA that modulates vascular and cardiac functions. J Med Chem 2016;59:2962–72.