Abstract
Over the last three decades, treatment of stroke and acute myocardial infarction (AMI) has been improved, but it has stagnated in the last few years. Patients with stroke and AMI are admitted with formed ischemic injury of the brain or the heart, thereby it is difficult to affect this injury. However, it was possible to affect reperfusion injury of the brain or the heart. Ischemic damage to the lung is observed in pulmonary embolism. Ischemia and reperfusion of kidneys are observed in kidney transplantation. Significant progress in an increase in the efficacy of kidney transplantation, in treatment of stroke, pulmonary embolism, and AMI can be achieved through the development of novel drugs capable of preventing reperfusion injury of the brain or the heart with high efficiency. Synthetic apelin analogues with a long half-life could be prototypes of such drugs. It was found that apelins can increase tolerance of the heart, the brain, the lung, and the intestine to ischemia/reperfusion (I/R). Protein kinases are involved in the neuroprotective, cardioprotective, renoprotective, and pulmonoprotective effects of apelins. Mitochondrial permeability transition pore and ATP-sensitive K+ channels are also involved in the protective effects of apelins. Apelins inhibit apoptosis and ferroptosis. Apelins activate autophagy of cardiomyocytes. Enzyme-resistant apelin analogues are perspective peptides for treatment of AMI, stroke, and I/R injury of lungs and kidneys.
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References
Abbasloo E, Najafipour H, Vakili A (2020) Chronic treatment with apelin, losartan and their combination reduces myocardial infarct size and improves cardiac mechanical function. Clin Exp Pharmacol Physiol 47(3):393–402. https://doi.org/10.1111/1440-1681.13195
Acele A, Bulut A, Donmez Y, Koc M (2020) Serum Elabela Level significantly increased in patients with Complete Heart Block. Brazilian J Cardiovasc Surg 35(5):683–688. https://doi.org/10.21470/1678-9741-2019-0461
An S, Wang X, Shi H, Zhang X, Meng H, Li W, Chen D, Ge J (2020) Apelin protects against ischemia-reperfusion injury in diabetic myocardium via inhibiting apoptosis and oxidative stress through PI3K and p38-MAPK signaling pathways. Aging 12(24):25120–25137. https://doi.org/10.18632/aging.104106
Arani Hessari F, Sharifi M, Yousefifard M, Gholamzadeh R, Nazarinia D, Aboutaleb N (2022) Apelin-13 attenuates cerebral ischemia/reperfusion injury through regulating inflammation and targeting the JAK2/STAT3 signaling pathway. J Chem Neuroanat 126:102171. https://doi.org/10.1016/j.jchemneu.2022.102171
Azizi Y, Faghihi M, Imani A, Roghani M, Nazari A (2013) Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. Peptides 46:76–82. https://doi.org/10.1016/j.peptides.2013.05.006
Azizi Y, Imani A, Fanaei H, Khamse S, Parvizi MR, Faghihi M (2017) Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats’ hearts. Kardiologia Polska 75(6):605–613. https://doi.org/10.5603/KP.a2017.0022
Bai B, Cai X, Jiang Y, Karteris E, Chen J (2014) Heterodimerization of apelin receptor and neurotensin receptor 1 induces phosphorylation of ERK(1/2) and cell proliferation via Gαq-mediated mechanism. J Cell Mol Med 18(10):2071–2081. https://doi.org/10.1111/jcmm.12404
Basir MB, Lemor A, Gorgis S, Taylor AM, Tehrani B, Truesdell AG, Bharadwaj A, Kolski B, Patel K, Gelormini J, Todd J, Lasorda D, Smith C, Riley R, Marso S, Federici R, Kapur NK, O’Neill WW, Investigators (2022) Vasopressors independently associated with mortality in acute myocardial infarction and cardiogenic shock. Catheter Cardiovasc Interv 99(3):650–657. https://doi.org/10.1002/ccd.29895
Becatti M, Taddei N, Cecchi C, Nassi N, Nassi PA, Fiorillo C (2012) SIRT1 modulates MAPK pathways in ischemic-reperfused cardiomyocytes. Cell Mol Life Sci 69(13):2245–2260. https://doi.org/10.1007/s00018-012-0925-5
Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, Woo YJ (2004) Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 110(11 Suppl 1):II187–193. https://doi.org/10.1161/01.CIR.0000138382.57325.5c
Bircan B, Çakır M, Kırbağ S, Gül HF (2016) Effect of apelin hormone on renal ischemia/reperfusion induced oxidative damage in rats. Ren Fail 38(7):1122–1128. https://doi.org/10.1080/0886022X.2016.1184957
Birsen İ, İzgüt-Uysal VN, Soylu H, Üstünel İ (2020) The effect of apelin-13 on gastric ischemia/reperfusion injury: the roles of sensory nerves and vagus nerve. Can J Physiol Pharmacol 98(5):282–295. https://doi.org/10.1139/cjpp-2019-0502
Boal F, Roumegoux J, Alfarano C, Timotin A, Calise D, Anesia R, Drougard A, Knauf C, Lagente C, Roncalli J, Desmoulin F, Tronchere H, Valet P, Parini A, Kunduzova O (2015) Apelin regulates FoxO3 translocation to mediate cardioprotective responses to myocardial injury and obesity. Sci Rep 5:16104. https://doi.org/10.1038/srep16104
Boucher J, Masri B, Daviaud D, Gesta S, Guigné C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpéné C, Audigier Y, Saulnier-Blache J-S, Valet P (2005) Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 146(4):1764–1771. https://doi.org/10.1210/en.2004-1427
Bülbül M, Sinen O, Bayramoğlu O, Akkoyunlu G (2020) Enteric apelin enhances the stress-induced stimulation of colonic motor functions. Stress 23(2):201–212. https://doi.org/10.1080/10253890.2019.1658739
Chapman NA, Dupré DJ, Rainey JK (2014) The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR. Biochemistry and Cell Biology = Biochimie. Et Biol Cellulaire 92(6):431–440. https://doi.org/10.1139/bcb-2014-0072
Chen MM, Ashley EA, Deng DXF, Tsalenko A, Deng A, Tabibiazar R, Ben-Dor A, Fenster B, Yang E, King JY, Fowler M, Robbins R, Johnson FL, Bruhn L, McDonagh T, Dargie H, Yakhini Z, Tsao PS, Quertermous T (2003) Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108(12):1432–1439. https://doi.org/10.1161/01.CIR.0000091235.94914.75
Chen H, Wan D, Wang L, Peng A, Xiao H, Petersen RB, Liu C, Zheng L, Huang K (2015) Apelin protects against acute renal injury by inhibiting TGF-β1. Biochim Biophys Acta 1852(7):1278–1287. https://doi.org/10.1016/j.bbadis.2015.02.013
Chen Y, Qiao X, Zhang L, Li X, Liu Q (2020a) Apelin-13 regulates angiotensin ii-induced Cx43 downregulation and autophagy via the AMPK/mTOR signaling pathway in HL-1 cells. Physiol Res 69(5):813–822. https://doi.org/10.33549/physiolres.934488
Chen P, Wang Y, Chen L, Song N, Xie J (2020b) Apelin-13 protects dopaminergic neurons against Rotenone-Induced neurotoxicity through the AMPK/mTOR/ULK-1 mediated autophagy activation. Int J Mol Sci 21(21):8376. https://doi.org/10.3390/ijms21218376
Chng SC, Ho L, Tian J, Reversade B (2013) ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell 27(6):672–680. https://doi.org/10.1016/j.devcel.2013.11.002
Chu H, Yang X, Huang C, Gao Z, Tang Y, Dong Q (2017) Apelin-13 protects against ischemic blood-brain barrier damage through the effects of Aquaporin-4. Cerebrovasc Dis 44(1–2):10–25. https://doi.org/10.1159/000460261
Collino M, Thiemermann C, Cerami A, Brines M (2015) Flipping the molecular switch for innate protection and repair of tissues: long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther 151:32–40. https://doi.org/10.1016/j.pharmthera.2015.02.005
de Oliveira AA, Vergara A, Wang X, Vederas JC, Oudit GY (2022) Apelin pathway in cardiovascular, kidney, and metabolic diseases: therapeutic role of apelin analogs and apelin receptor agonists. Peptides 147:170697. https://doi.org/10.1016/j.peptides.2021.170697. https://www.sciencedirect.com/science/article/pii/S0196978121002059
Deng C, Chen H, Yang N, Feng Y, Hsueh AJW (2015) Apela regulates Fluid Homeostasis by binding to the APJ receptor to activate Gi Signaling. J Biol Chem 290(30):18261–18268. https://doi.org/10.1074/jbc.M115.648238
Ding M, Lei J, Han H, Li W, Qu Y, Fu E, Fu F, Wang X (2015) SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats. Cardiovasc Diabetol 14:143. https://doi.org/10.1186/s12933-015-0299-8
Dönmez Y, Acele A (2019) Increased elabela levels in the acute ST segment elevation myocardial infarction patients. Medicine 98(43):e17645. https://doi.org/10.1097/MD.0000000000017645
Duan J, Cui J, Yang Z, Guo C, Cao J, Xi M, Weng Y, Yin Y, Wang Y, Wei G, Qiao B, Wen A (2019) Neuroprotective effect of Apelin 13 on ischemic stroke by activating AMPK/GSK-3β/Nrf2 signaling. J Neuroinflamm 16(1):24. https://doi.org/10.1186/s12974-019-1406-7
Fan X-F, Xue F, Zhang Y-Q, Xing X-P, Liu H, Mao S-Z, Kong X-X, Gao Y-Q, Liu SF, Gong Y-S (2015) The Apelin-APJ axis is an endogenous counterinjury mechanism in experimental acute lung injury. Chest 147(4):969–978. https://doi.org/10.1378/chest.14-1426
Folino A, Accomasso L, Giachino C, Montarolo PG, Losano G, Pagliaro P, Rastaldo R (2018) Apelin-induced cardioprotection against ischaemia/reperfusion injury: Roles of epidermal growth factor and Src. Acta Physiologica (Oxford England) 222(2):e12924
Garcia S, Schmidt CW, Garberich R, Henry TD, Bradley SM, Brilakis ES, Burke N, Chavez IJ, Eckman P, Gössl M, Mooney MR, Newell MC, Poulose AK, Sorajja P, Traverse JH, Wang YL, Sharkey SW (2021) Temporal changes in patient characteristics and outcomes in ST-segment elevation myocardial infarction 2003–2018. Catheter Cardiovasc Interv 97(6):1109–1117. https://doi.org/10.1002/ccd.28901
Gargalovic P, Wong P, Onorato J, Finlay H, Wang T, Yan M, Crain E, St-Onge S, Héroux M, Bouvier M, Xu C, Chen X-Q, Generaux C, Lawrence M, Wexler R, Gordon D (2021) In Vitro and in vivo evaluation of a small-molecule APJ (apelin receptor) agonist, BMS-986224, as a potential treatment for heart failure. Circ Heart Fail 14(3):e007351. https://doi.org/10.1161/CIRCHEARTFAILURE.120.007351
Gholampour F, Bagheri A, Barati A, Masoudi R, Owji SM (2020) Remote ischemic perconditioning modulates apelin expression after renal ischemia-reperfusion Injury. J Surg Res 247:429–437. https://doi.org/10.1016/j.jss.2019.09.063
Gholamzadeh R, Aboutaleb N, Nazarinia D (2021) Intravenous injection of apelin-13 improves sensory-motor balance deficits caused by cerebral ischemic reperfusion injury in male wistar rats via restoration of nitric oxide. J Chem Neuroanat 112:101886. https://doi.org/10.1016/j.jchemneu.2020.101886
Gholamzadeh R, Ramezani F, Tehrani PM, Aboutaleb N (2021b) Apelin-13 attenuates injury following ischemic stroke by targeting matrix metalloproteinases (MMP), endothelin- B receptor, occludin/claudin-5 and oxidative stress. J Chem Neuroanat 118:102015. https://doi.org/10.1016/j.jchemneu.2021.102015
Giricz Z, Varga ZV, Koncsos G, Nagy CT, Görbe A, Mentzer RM, Gottlieb RA, Ferdinandy P (2017) Autophagosome formation is required for cardioprotection by chloramphenicol. Life Sci 186:11–16. https://doi.org/10.1016/j.lfs.2017.07.035
Gu Q, Zhai L, Feng X, Chen J, Miao Z, Ren L, Qian X, Yu J, Li Y, Xu X, Liu C-F (2013) Apelin-36, a potent peptide, protects against ischemic brain injury by activating the PI3K/Akt pathway. Neurochem Int 63(6):535–540. https://doi.org/10.1016/j.neuint.2013.09.017
Guzeldag S (2022) The Effect of Age and Sex on Ischemıc Stroke: a Sıngle-Centred Neuro-Intensıve Care Unıt Experıence. Acta Neurol Taiwanica 31(4):145–153
Hage A, Stevens L-M, Ouzounian M, Chung J, El-Hamamsy I, Chauvette V, Dagenais F, Cartier A, Peterson MD, Boodhwani M, Guo M, Bozinovski J, Moon MC, White A, Kumar K, Lodewyks C, Bittira B, Payne D, Chu MWA (2020) Impact of brain protection strategies on mortality and stroke in patients undergoing aortic arch repair with hypothermic circulatory arrest: evidence from the Canadian thoracic aortic collaborative. Eur J Cardio-Thoracic Surgery: Official J Eur Association Cardio-Thoracic Surg 58(1):95–103. https://doi.org/10.1093/ejcts/ezaa023
Hou X, Zeng H, He X, Chen JX (2015a) Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. J Cell Mol Med 19(1):53–61. https://doi.org/10.1111/jcmm.12453
Hou X, Zeng H, Tuo Q-H, Liao D-F, Chen J-X (2015b) Apelin Gene Therapy increases Autophagy via activation of Sirtuin 3 in Diabetic Heart. Diabetes Res (Fairfax Va) 1(4):84–91. https://doi.org/10.17140/DROJ-1-115
Hsu CP, Zhai P, Yamamoto T, Maejima Y, Matsushima S, Hariharan N, Shao D, Takagi H, Oka S, Sadoshima J (2010) Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation 122(21):2170–2182. https://doi.org/10.1161/CIRCULATIONAHA.110.958033
Hu G, Wang Z, Zhang R, Sun W, Chen X (2021) The role of Apelin/Apelin Receptor in Energy Metabolism and Water Homeostasis: a Comprehensive Narrative Review. Front Physiol 12:632886. https://doi.org/10.3389/fphys.2021.632886
Huang J, Klionsky DJ (2007) Autophagy and human disease. Cell Cycle (Georgetown Tex) 6(15):1837–1849. https://doi.org/10.4161/cc.6.15.4511
Jin Q, Ma F, Liu T, Yang L, Mao H, Wang Y, Peng L, Li P, Zhan Y (2024) Sirtuins in kidney diseases: potential mechanism and therapeutic targets. Cell Commun Signal. 22(1):114
Kalea AZ, Batlle D (2010) Apelin and ACE2 in cardiovascular disease. Curr Opin Investig Drugs 11(3):273–282
Kawamata Y, Habata Y, Fukusumi S, Hosoya M, Fujii R, Hinuma S, Nishizawa N, Kitada C, Onda H, Nishimura O, Fujino M (2001) Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 1538(2–3):162–171. https://doi.org/10.1016/s0167-4889(00)00143-9
Khaksari M, Aboutaleb N, Nasirinezhad F, Vakili A, Madjd Z (2012) Apelin-13 protects the brain against ischemic reperfusion injury and cerebral edema in a transient model of focal cerebral ischemia. J Mol Neuroscience: MN 48(1):201–208. https://doi.org/10.1007/s12031-012-9808-3
Kleinz MJ, Baxter GF (2008) Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase. Regul Pept 146(1–3):271–277. https://doi.org/10.1016/j.regpep.2007.10.002
Kutlay O (2018) The impact of apelin-36 on isolated rat hearts as a member of apelin family. Bratisl Lek Listy 119(10):625–629. https://doi.org/10.4149/BLL_2018_111
Li C, Miao X, Wang S, Liu Y, Sun J, Liu Q, Cai L, Wang Y (2021) Elabela may regulate SIRT3-mediated inhibition of oxidative stress through Foxo3a deacetylation preventing diabetic-induced myocardial injury. J Cell Mol Med 25(1):323–332. https://doi.org/10.1111/jcmm.16052
Lio KU, O’Corragain O, Bashir R, Brosnahan S, Cohen G, Lakhter V, Panaro J, Rivera-Lebron B, Rali P (2022) Clinical outcomes and factors associated with pulmonary infarction following acute pulmonary embolism: a retrospective observational study at a US academic centre. BMJ Open 12(12):e067579. https://doi.org/10.1136/bmjopen-2022-067579
Liu H-T, Chen M, Yu J, Li W-J, Tao L, Li Y, Guo W-Y, Wang H-C (2015) Serum apelin level predicts the major adverse cardiac events in patients with ST elevation myocardial infarction receiving percutaneous coronary intervention. Medicine 94(4):e449. https://doi.org/10.1097/MD.0000000000000449
Liu D-R, Hu W, Chen G-Z (2018) Apelin-12 exerts neuroprotective effect against ischemia-reperfusion injury by inhibiting JNK and P38MAPK signaling pathway in mouse. Eur Rev Med Pharmacol Sci 22(12):3888–3895. https://doi.org/10.26355/eurrev_201806_15273
Ma X, Liu H, Foyil SR, Godar RJ, Weinheimer CJ, Hill JA, Diwan A (2012) Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation 125(25):3170–3181. https://doi.org/10.1161/CIRCULATIONAHA.111.041814
Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP (2009) [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertens (Dallas Tex : 1979) 54(3):598–604. https://doi.org/10.1161/HYPERTENSIONAHA.109.134619
Martini V, Lederer A-K, Fink J, Chikhladze S, Utzolino S, Fichtner-Feigl S, Kousoulas L (2022) Clinical characteristics and outcome of patients with acute mesenteric ischemia: a retrospective cohort analysis. Langenbeck’s Archives Surg 407(3):1225–1232. https://doi.org/10.1007/s00423-021-02423-2
Masri B, Morin N, Pedebernade L, Knibiehler B, Audigier Y (2006) The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J Biol Chem 281(27):18317–18326. https://doi.org/10.1074/jbc.M600606200
Megaly M, Pershad A, Glogoza M, Elbadawi A, Omer M, Saad M, Mentias A, Elgendy I, Burke MN, Capodanno D, Brilakis ES (2021) Use of intravascular imaging in patients with ST-Segment Elevation Acute myocardial infarction. Cardiovasc Revascularization Medicine: Including Mol Interventions 30:59–64. https://doi.org/10.1016/j.carrev.2020.09.032
Motova AV, Karetnikova VN, Osokina AV, Polikutina OM, Barbarash OL (2022) Type 2 myocardial infarction: diagnostic features in real clinical practice. Siberian J Clin Exper Med 37(3):75–82. https://doi.org/10.29001/2073-8552-2022-37-3-75-82
Mughal A, Sun C, O’Rourke ST (2018) Activation of large conductance, calcium-activated Potassium channels by nitric oxide mediates Apelin-Induced relaxation of isolated rat coronary arteries. J Pharmacol Exp Ther 366(2):265–273. https://doi.org/10.1124/jpet.118.248682
Nadtochiy SM, Yao H, McBurney MW, Gu W, Guarente L, Rahman I, Brookes PS (2011) SIRT1-mediated acute cardioprotection. Am J Physiol Heart Circ Physiol 301(4):H1506–H1512. https://doi.org/10.1152/ajpheart.00587.2011
Nasseri B, Zareian P, Alizade H (2020) Apelin attenuates streptozotocin-induced learning and memory impairment by modulating necroptosis signaling pathway. Int Immunopharmacol 84:106546. https://doi.org/10.1016/j.intimp.2020.106546
Nguyen AQ, Cherry BH, Scott GF, Ryou M-G, Mallet RT (2014) Erythropoietin: powerful protection of ischemic and post-ischemic brain. Experimental Biology Med (Maywood N J) 239(11):1461–1475. https://doi.org/10.1177/1535370214523703
O’Dowd BF, Heiber M, Chan A, Heng HHQ, Tsui L-C, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T (1993) A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136(1):355–360. https://doi.org/10.1016/0378-1119(93)90495-O
O’Harte FPM, Parthsarathy V, Hogg C, Flatt PR (2018) Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions. Peptides 100:219–228. https://doi.org/10.1016/j.peptides.2017.12.004
Pagliaro P, Penna C (2005) Rethinking the renin-angiotensin system and its role in Cardiovascular Regulation. Cardiovasc Drugs Ther 19(1):77–87. https://doi.org/10.1007/s10557-005-6900-8
Perjés Á, Skoumal R, Tenhunen O, Kónyi A, Simon M, Horváth IG, Kerkelä R, Ruskoaho H, Szokodi I (2014) Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms. PLoS ONE 9(4):e93473. https://doi.org/10.1371/journal.pone.0093473
Pisarenko OI, Shulzhenko VS, Pelogeĭkina IA, Studneva IM, Kkhatri DN, Bespalova ZD, Az’muko AA, Sidorova MV, Pal’keeva ME (2010) [Effects of exogenous apelin-12 on functional and metabolic recovery of isolated rat heart after ischemia]. Kardiologiia 50(10):44–49
Pisarenko OI, Serebryakova LI, Pelogeykina YA, Studneva IM, Khatri DN, Tskitishvili OV, Bespalova ZD, Az’muko AA, Sidorova MV, Pal’keeva ME (2011) In vivo reduction of reperfusion injury to the heart with apelin-12 peptide in rats. Bull Exp Biol Med 152(1):79–82. https://doi.org/10.1007/s10517-011-1459-9
Pisarenko OI, Serebriakova LI, Pelogeĭkina IA, Studneva IM, Kkhatri DN, Tskitishvili OV, Bespalova ZD, Az’muko AA, Sidorova MV, Pal’keeva ME, Chazov EI (2012a) [Involvement of NO-dependent mechanisms of apelin action in myocardial protection against ischemia/reperfusion damage]. Kardiologiia 52(2):52–58
Pisarenko OI, Pelogeĭkina IA, Shul’zhenko VS, Studneva IM, Bespalova ZD, Az’muko AA, Sidorova MV, Pal’keeva ME (2012c) [The influence of inhibiting no formation on metabolic recovery of ischemic rat heart by apelin-12]. Biomeditsinskaia Khimiia 58(6):702–711. https://doi.org/10.18097/pbmc20125806702
Pisarenko OI, Bespalova ZD, Lankin VZ, Timoshin AA, Serebriakova LI, Shul’zhenko VS, Pelogeĭkina IA, Studneva IM, Tskitishvili OV, Az’muko AA, Sidorova MV, Pal’keeva ME, Konovalova GG, Chazov EI (2013) [Antioxidant properties of apelin-12 and its structural analogue in experimental ischemia and reperfusion]. Kardiologiia 53(5):61–67
Pisarenko OI, Lankin VZ, Konovalova GG, Serebryakova LI, Shulzhenko VS, Timoshin AA, Tskitishvili OV, Pelogeykina YA, Studneva IM (2014) Apelin-12 and its structural analog enhance antioxidant defense in experimental myocardial ischemia and reperfusion. Mol Cell Biochem 391(1–2):241–250. https://doi.org/10.1007/s11010-014-2008-4
Pisarenko OI, Shulzhenko VS, Pelogeykina YA, Studneva IM (2015) Enhancement of crystalloid cardioplegic protection by structural analogs of apelin-12. J Surg Res 194(1):18–24. https://doi.org/10.1016/j.jss.2014.11.007
Pisarenko OI, Shulzhenko VS, Studneva IM, Serebryakova LI, Pelogeykina YA, Veselova OM (2015b) Signaling pathways of a structural analogue of apelin-12 involved in myocardial protection against ischemia/reperfusion injury. Peptides 73:67–76. https://doi.org/10.1016/j.peptides.2015.09.001
Pisarenko O, Shulzhenko V, Studneva I, Pelogeykina Y, Timoshin A, Anesia R, Valet P, Parini A, Kunduzova O (2015c) Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury. Br J Pharmacol 172(12):2933–2945. https://doi.org/10.1111/bph.13038
Popov SV, Mukhomedzyanov AV, Voronkov NS, Derkachev IA, Boshchenko AA, Fu F, Sufianova GZ, Khlestkina MS, Maslov LN (2022) Regulation of autophagy of the heart in ischemia and reperfusion. Apoptosis: Int J Program Cell Death. https://doi.org/10.1007/s10495-022-01786-1
Prabhakaran S, Ruff I, Bernstein RA (2015) Acute stroke intervention: a systematic review. JAMA 313(14):1451–1462. https://doi.org/10.1001/jama.2015.3058
Rastaldo R, Cappello S, Folino A, Berta GN, Sprio AE, Losano G, Samaja M, Pagliaro P (2011) Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. Am J Physiol Heart Circ Physiol 300(6):H2308–2315. https://doi.org/10.1152/ajpheart.01177.2010
Reed AB, Lanman BA, Holder JR, Yang BH, Ma J, Humphreys SC, Wang Z, Chan JCY, Miranda LP, Swaminath G, Allen JG (2020) Half-life extension of peptidic APJ agonists by N-terminal lipid conjugation. Bioorg Med Chem Lett 30(21):127499. https://doi.org/10.1016/j.bmcl.2020.127499
Rostamzadeh F, Najafipour H, Yeganeh-Hajahmadi M, Esmaeili-Mahani S, Joukar S, Iranpour M (2017) Heterodimerization of apelin and opioid receptors and cardiac inotropic and lusitropic effects of apelin in 2K1C hypertension: role of pERK1/2 and PKC. Life Sci 191:24–33. https://doi.org/10.1016/j.lfs.2017.09.044
Sağıroğlu T, Oğuz S, Sağıroğlu G, Copuroğlu E, Yalta T, Sayhan MB, Yağcı MA (2012) The effects of apelin on mesenteric ischemia and reperfusion damage in an experimental rat model. Balkan Med J 29(2):148–152. https://doi.org/10.5152/balkanmedj.2011.036
Sala-Mercado JA, Wider J, Undyala VVR, Jahania S, Yoo W, Mentzer RM, Gottlieb RA, Przyklenk K (2010) Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation 122(11 Suppl):S179–184. https://doi.org/10.1161/CIRCULATIONAHA.109.928242
Sambola A, Elola FJ, Buera I, Fernández C, Bernal JL, Ariza A, Brindis R, Bueno H, Rodríguez-Padial L, Marín F, Barrabés JA, Hsia R, Anguita M (2021) Sex bias in admission to tertiary-care centres for acute myocardial infarction and cardiogenic shock. Eur J Clin Invest 51(7):e13526. https://doi.org/10.1111/eci.13526
Sans-Roselló J, Casals G, Rossello X, González de la Presa B, Vila M, Duran-Cambra A, Morales-Ruiz M, Ferrero-Gregori A, Jiménez W, Sionis A (2017) Prognostic value of plasma apelin concentrations at admission in patients with ST-segment elevation acute myocardial infarction. Clin Biochem 50(6):279–284. https://doi.org/10.1016/j.clinbiochem.2016.11.018
Sato T, Kadowaki A, Suzuki T, Ito H, Watanabe H, Imai Y, Kuba K (2019) Loss of Apelin augments angiotensin II-Induced Cardiac Dysfunction and pathological remodeling. Int J Mol Sci 20(2):239. https://doi.org/10.3390/ijms20020239
Sekerci R, Acar N, Tepekoy F, Ustunel I, Keles-Celik N (2018) Apelin/APJ expression in the heart and kidneys of hypertensive rats. Acta Histochem 120(3):196–204. https://doi.org/10.1016/j.acthis.2018.01.007
Shao Z-Q, Dou S-S, Zhu J-G, Wang H-Q, Wang C-M, Cheng B-H, Bai B (2021a) Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury. Neural Regeneration Res 16(6):1044–1051. https://doi.org/10.4103/1673-5374.300725
Shao Z, Dou S, Zhu J, Wang H, Xu D, Wang C, Cheng B, Bai B (2021b) Apelin-36 protects HT22 cells against oxygen-glucose Deprivation/Reperfusion-Induced oxidative stress and mitochondrial dysfunction by promoting SIRT1-Mediated PINK1/Parkin-Dependent Mitophagy. Neurotox Res 39(3):740–753. https://doi.org/10.1007/s12640-021-00338-w
Simpkin JC, Yellon DM, Davidson SM, Lim SY, Wynne AM, Smith CCT (2007) Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Res Cardiol 102(6):518–528. https://doi.org/10.1007/s00395-007-0671-2
Smith CCT, Mocanu MM, Bowen J, Wynne AM, Simpkin JC, Dixon RA, Cooper MB, Yellon DM (2007) Temporal changes in myocardial salvage kinases during reperfusion following ischemia: studies involving the cardioprotective adipocytokine apelin. Cardiovasc Drugs Ther 21(6):409–414. https://doi.org/10.1007/s10557-007-6054-y
Swinarska JT, Stratta RJ, Rogers J, Chang A, Farney AC, Orlando G, Reeves-Daniel A, Gurram V, Gautreaux MD, Jay CL (2021) Early graft loss after deceased-donor kidney transplantation: what are the consequences? J Am Coll Surg 232(4):493–502. https://doi.org/10.1016/j.jamcollsurg.2020.12.005
Szokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysä J, Tóth M, Ruskoaho H (2002) Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circul Res 91(5):434–440. https://doi.org/10.1161/01.res.0000033522.37861.69
Tao J, Zhu W, Li Y, Xin P, Li J, Liu M, Li J, Redington AN, Wei M (2011) Apelin-13 protects the heart against ischemia-reperfusion injury through inhibition of ER-dependent apoptotic pathways in a time-dependent fashion. Am J Physiol Heart Circ Physiol 301(4):H1471–1486. https://doi.org/10.1152/ajpheart.00097.2011
Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251(2):471–476. https://doi.org/10.1006/bbrc.1998.9489
Than A, He HL, Chua SH, Xu D, Sun L, Leow MK-S, Chen P (2015) Apelin enhances Brown Adipogenesis and Browning of White adipocytes. J Biol Chem 290(23):14679–14691. https://doi.org/10.1074/jbc.M115.643817
Ustunel I, Acar N, Gemici B, Ozbey O, Edizer I, Soylu H, Tepekoy F, Izgut-Uysal VN (2014) The effects of water immersion and restraint stress on the expressions of apelin, apelin receptor (APJR) and apoptosis rate in the rat heart. Acta Histochem 116(5):675–681. https://doi.org/10.1016/j.acthis.2013.12.004
Vyshlov EV, Alexeeva YA, Ussov WY, Mochula OV, Ryabov VV (2022) Phenomena of microvascular myocardial injury in patients with primary ST-segment elevation myocardial infarction: prevalence and association with clinical characteristics. Siberian J Clin Exper Med 37(1):36–46. https://doi.org/10.29001/2073-8552-2021-36-4-36-46
Wang C, Du J-F, Wu F, Wang H-C (2008) 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 294(6):H2540-2546. https://doi.org/10.1152/ajpheart.00046.2008
Wang G, Kundu R, Han S, Qi X, Englander EW, Quertermous T, Greeley GH (2009) Ontogeny of apelin and its receptor in the rodent gastrointestinal tract. Regul Pept 158(1–3):32–39. https://doi.org/10.1016/j.regpep.2009.07.016
Wang W, Bodiga S, Das SK, Lo J, Patel V, Oudit GY (2012) Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev 17(4–5):683–691. https://doi.org/10.1007/s10741-011-9259-x
Wang C, Liu N, Luan R, Li Y, Wang D, Zou W, Xing Y, Tao L, Cao F, Wang H (2013a) Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia-reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. Cardiovascular Res 100(1):114–124. https://doi.org/10.1093/cvr/cvt160
Wang W, McKinnie SMK, Patel VB, Haddad G, Wang Z, Zhabyeyev P, Das SK, Basu R, McLean B, Kandalam V, Penninger JM, Kassiri Z, Vederas JC, Murray AG, Oudit GY (2013b) Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic apelin analogues. J Am Heart Association 2(4):e000249. https://doi.org/10.1161/JAHA.113.000249
Wang Q, Xu J, Li X, Liu Z, Han Y, Xu X, Li X, Tang Y, Liu Y, Yu T, Li X (2019) Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway. J Cell Physiol 234(12):23495–23506. https://doi.org/10.1002/jcp.28918
Wang K, Ju Z, Chen C, Fan S, Pei L, Feng C, Wang F, Cui H, Zhou J (2020a) Cardioprotective effect of electroacupuncture in cardiopulmonary bypass through apelin/APJ signaling. Life Sci 242:117208. https://doi.org/10.1016/j.lfs.2019.117208
Wang C, Xiong M, Yang C, Yang D, Zheng J, Fan Y, Wang S, Gai Y, Lan X, Chen H, Zheng L, Huang K (2020b) PEGylated and acylated Elabela Analogues Show enhanced receptor binding, prolonged Stability, and remedy of Acute kidney Injury. J Med Chem 63(24):16028–16042. https://doi.org/10.1021/acs.jmedchem.0c01913
Wang H, Cong L, Yin X, Zhang N, Zhu M, Sun T, Fan J, Xue F, Fan X, Gong Y (2022) The Apelin-APJ axis alleviates LPS-induced pulmonary fibrosis and endothelial mesenchymal transformation in mice by promoting angiotensin-converting enzyme 2. Cell Signal 98:110418. https://doi.org/10.1016/j.cellsig.2022.110418
Wang Z, Lin D, Cui B, Zhang D, Wu J, Ma J (2024) Melatonin protects against myocardial ischemia-reperfusion injury by inhibiting excessive mitophagy through the Apelin/SIRT3 signaling axis. Eur J Pharmacol 963:176292. https://doi.org/10.1016/j.ejphar.2023.176292
Wu G, Li L, Liao D, Wang Z (2015) [Protective effect of Apelin-13 on focal cerebral ischemia-reperfusion injury in rats]. Nan Fang Yi Ke Da Xue Xue Bao = J South Med Univ 35(9):1335–1339
Wu F, Qiu J, Fan Y, Zhang Q, Cheng B, Wu Y, Bai B (2018) Apelin-13 attenuates ER stress-mediated neuronal apoptosis by activating Gαi/Gαq-CK2 signaling in ischemic stroke. Exp Neurol 302:136–144. https://doi.org/10.1016/j.expneurol.2018.01.006
Xia F, Chen H, Jin Z, Fu Z (2021) Apelin-13 protects the lungs from ischemia-reperfusion injury by attenuating inflammatory and oxidative stress. Hum Exp Toxicol 40(4):685–694. https://doi.org/10.1177/0960327120961436
Xie F, Liu W, Feng F, Li X, He L, Lv D, Qin X, Li L, Li L, Chen L (2015) Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy. Acta Biochim Biophys Sin 47(12):969–980. https://doi.org/10.1093/abbs/gmv111
Xin Q, Cheng B, Pan Y, Liu H, Yang C, Chen J, Bai B (2015) Neuroprotective effects of apelin-13 on experimental ischemic stroke through suppression of inflammation. Peptides 63:55–62. https://doi.org/10.1016/j.peptides.2014.09.016
Xu F, Wu M, Lu X, Zhang H, Shi L, Xi Y, Zhou H, Wang J, Miao L, Gong D-W, Cui W (2022) Effect of Fc-Elabela-21 on renal ischemia/reperfusion injury in mice: mediation of anti-apoptotic effect via akt phosphorylation. Peptides 147:170682. https://doi.org/10.1016/j.peptides.2021.170682
Ya’qoub L, Gad M, Saad AM, Elgendy IY, Mahmoud AN (2021) National trends of utilization and readmission rates with intravascular ultrasound use for ST-elevation myocardial infarction. Catheter Cardiovasc Interven: Official J Soc Cardiac Angiogr Interven 98(1):1–9. https://doi.org/10.1002/ccd.29524
Yan X-G, Cheng B-H, Wang X, Ding L-C, Liu H-Q, Chen J, Bai B (2015) Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury. Neural Regen Res 10(5):766–771. https://doi.org/10.4103/1673-5374.157243
Yang Y, Zhang X, Cui H, Zhang C, Zhu C, Li L (2014) Apelin-13 protects the brain against ischemia/reperfusion injury through activating PI3K/Akt and ERK1/2 signaling pathways. Neurosci Lett 568:44–49. https://doi.org/10.1016/j.neulet.2014.03.037
Yang S, Li H, Tang L, Ge G, Ma J, Qiao Z, Liu H, Fang W (2015) Apelin-13 protects the heart against ischemia-reperfusion injury through the RISK-GSK-3β-mPTP pathway. Arch Med Sci: AMS 11(5):1065–1073. https://doi.org/10.5114/aoms.2015.54863
Yang Y, Zhang X-J, Li L-T, Cui H-Y, Zhang C, Zhu C-H, Miao J-Y (2016) Apelin-13 protects against apoptosis by activating AMP-activated protein kinase pathway in ischemia stroke. Peptides 75:96–100. https://doi.org/10.1016/j.peptides.2015.11.002
Ye Y, Cai Y, Xia E, Shi K, Jin Z, Chen H, Xia F, Xia Y, Papadimos TJ, Xu X, Liu L, Wang Q (2021) Apelin-13 reverses Bupivacaine-Induced Cardiotoxicity via the Adenosine Monophosphate-activated protein kinase pathway. Anesth Analg 133(4):1048–1059. https://doi.org/10.1213/ANE.0000000000005692
Yin L, Zhang P, Li C, Si J, Wang Y, Zhang X, Zhang D, Zhang H, Lin C (2018) Apelin–13 promotes cell proliferation in the H9c2 cardiomyoblast cell line by triggering extracellular signal–regulated kinase 1/2 and protein kinase B phosphorylation. Mol Med Rep 17(1):447–451. https://doi.org/10.3892/mmr.2017.7919
Yu P, Ma S, Dai X, Cao F (2020) Elabela alleviates myocardial ischemia reperfusion-induced apoptosis, fibrosis and mitochondrial dysfunction through PI3K/AKT signaling. Am J Transl Res 12(8):4467–4477
Yu Y, Yan Y, Niu F, Wang Y, Chen X, Su G, Liu Y, Zhao X, Qian L, Liu P, Xiong Y (2021) Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov 7(1):193. https://doi.org/10.1038/s41420-021-00579-w
Zeng XJ, Zhang LK, Wang HX, Lu LQ, Ma LQ, Tang CS (2009) Apelin protects heart against ischemia/reperfusion injury in rat. Peptides 30(6):1144–1152. https://doi.org/10.1016/j.peptides.2009.02.010
Zenkov NK, Kozhin PM, Chechushkov AV, Martinovich GG, Kandalintseva NV, Menshchikova EB (2017) Mazes of Nrf2 regulation. Biochem Biokhimiia 82(5):556–564. https://doi.org/10.1134/S0006297917050030
Zhang H, Gong D, Ni L, Shi L, Xu W, Shi M, Chen J, Ai Y, Zhang X (2018) Serum Elabela/Toddler Levels Are Associated with Albuminuria in patients with type 2 diabetes. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 48(3):1347–1354. https://doi.org/10.1159/000492093
Zhang X, Zhu Y, Zhou Y, Fei B (2020) Activation of Nrf2 signaling by apelin attenuates renal ischemia reperfusion injury in diabetic rats. Diabetes Metabol Syndr Obes: Targets Ther 13:2169–2177. https://doi.org/10.2147/DMSO.S246743
Zhang J, Chang H, Rockman C, Patel VI, Veeraswamy R, Berland T, Ramkhelawon B, Maldonado T, Cayne N, Jacobowitz G, Garg K (2022a) Hypogastric Artery Flow Interruption is Associated with increased mortality after Open Aortic Repair. Ann Vasc Surg 87:270–277. https://doi.org/10.1016/j.avsg.2022.05.010
Zhang R, Wu F, Cheng B, Wang C, Bai B, Chen J (2022b) Apelin-13 prevents the effects of oxygen-glucose deprivation/reperfusion on bEnd.3 cells by inhibiting AKT-mTOR signaling. Exp Biol Med (Maywood N J) 248:146–156
Zhang Z, Tang J, Song J, Xie M, Liu Y, Dong Z, Liu X, Li X, Zhang M, Chen Y, Shi H, Zhong J (2022c) Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling. Free Radic Biol Med 181:130–142. https://doi.org/10.1016/j.freeradbiomed.2022.01.020
Zhou Q, Cao J, Chen L (2016) Apelin/APJ system: a novel therapeutic target for oxidative stress-related inflammatory diseases (review). Int J Mol Med 37(5):1159–1169. https://doi.org/10.3892/ijmm.2016.2544
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The authors are grateful to Ivan A. Derkachev, Alexey L. Maslov, and Philip Ilinykh for information support.
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The review article was supported by Russian Science Foundation (grant 22-15-00048). The chapter “The synthetic analogues of apelins” was supported by state assignment 122020300042-4.
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Popov, S.V., Maslov, L.N., Mukhomedzyanov, A.V. et al. Apelin is Peptide Increasing Tolerance of Organs and Cells to Hypoxia and Reoxygenation. The Signaling Mechanism. Int J Pept Res Ther 30, 21 (2024). https://doi.org/10.1007/s10989-024-10599-6
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DOI: https://doi.org/10.1007/s10989-024-10599-6