APELIN/APJ 在呼吸系统疾病中的研究进展_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

贾盼红 ¹ , 唐欢欢 ¹ , 李琪 ^1,2,3 ,  周向东 ^1,2,3

1. ;
2. ;
3. ;

Corresponding author：

周向东, Email: zxd999@263.net

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DOI：

10.7507/1671-6205.202012091

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Citation： 贾盼红, 唐欢欢, 李琪, 周向东. APELIN/APJ 在呼吸系统疾病中的研究进展. Chinese Journal of Respiratory and Critical Care Medicine, 2021, 20(7): 528-532. doi: 10.7507/1671-6205.202012091 Copy

1.	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): 355-360.
2.	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): 471-476.
3.	Medhurst AD, Jennings CA, Robbins MJ, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. Neurochem, 2019, 84(5): 1162-1172.
4.	Cano Martinez LJ, Coral Vazquez RM, Mendez JP, et al. Canto P Serum concentrations of apelin-17 isoform vary in accordance to blood pressure categories in individuals with obesity class 3. Clin Exp Hypertens, 2019, 41(2): 168-173.
5.	Zhou Q, Xu J, Liu M, et al. Warburg effect is involved inapelin13 induced human aorticvascular smooth muscle cells proliferation. Cell Physiol, 2019, 27(10): 921-932.
6.	Xie F, Liu W, Feng F, et al. Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy. Acta Biochim Biophys Sin, 2019, 47(12): 969-980.
7.	Liu MQ, Chen Z, Chen LX, et al. Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases. Acta Pharmacol Sin, 2016, 37(4): 425-443.
8.	Zhang H, Chen S, Zeng M, et al. Apelin-13 administration protects against LPS induced acute lung injury by inhibiting NF-kappaB pathway and NLRP3 infammasome activation. Cell Physiol Biochem, 2018, 49(5): 1918-1932.
9.	Liu M, Li H, Zhou Q, et al. ROS-Autophagy pathway mediates monocytes-human umbilical vein endothelial cells adhesion induced by apelin-13. Cell Physiol, 2019, 233(10): 6839-6850.
10.	Ureche C, Tapoi L, Volovat S, et al. Cardioprotective apelin efects and the cardiac-renal axis: review of existing science and potential therapeutic applications of synthetic and native regulated apelin. Hum Hypertens, 2019, 62(5): 962-972.
11.	Besserer-Offroy É, Bérubé P, Côté J, et al. The hypotensive effect of activated apelin receptor is correlated with β-arrestin recruitment. Pharmacol Res, 2018, 131: 7-16.
12.	Furuya M, Okuda M, Usui H, et al. Expression of angiotensin Ⅱ receptor-like 1 in the placentas of pregnancy induced hypertension. Int J Gynecol Pathol, 2012, 31(3): 227-235.
13.	Najafpour H, Soltani Hekmat A, Nekooian AA, et al. 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(1-3): 43-50.
14.	Zhou Q, Chen L, Tang M, et al. Apelin/APJ system: a novel promising target for anti-aging intervention. Clin Chim Acta, 2018, 487: 233-240.
15.	Vinel C, Lukjanenko L, Batut A, et al. The exerkine apelin reverses age-associated sarcopenia. Nat Med, 2018, 24(9): 1360-1371.
16.	Ji W, Shi H, Shen H, et al. Mechanism of KLF4 protection against acute liver injury via inhibition of apelin signaling. Oxid Med Cell Longev, 2019, 2019: 6140360.
17.	Huang Z, Wu L, Chen L. Apelin/APJ system: a novel potential therapy target for kidney disease. J Cell Physiol, 2018, 233(5): 3892-3900.
18.	He S, Li J, Wang J, et al. Hypoxia exposure alleviates impaired muscular metabolism, glucose tolerance, and aerobic capacity in apelin-knockout mice. FEBS Open Bio, 2019, 9(3): 498-509.
19.	Kawamata Y, Habata Y, Fukusumi S, et al. Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta, 2001, 1538(2-3): 162-171.
20.	Kleinz MJ, Davenport AP. Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regul Pept, 2004, 118(3): 119-125.
21.	Goetze JP, Rehfeld JF, Carlsen J, et al. Apelin: anew plasma marker of cardiopulmonary disease. Regul Pept, 2006, 133(1-3): 134-138.
22.	Fan XF, Xue F, Zhang YQ, et al. The Apelin-APJ axis is an endogenous counterinjury mechanism in experimental acute lung injury. Chest, 2015, 147(4): 969-978.
23.	Andersen CU, Hilberg O, Mellemkjær S, et al. Apelin and pulmonary hypertension. Pulm Circ, 2011, 1(3): 334-346.
24.	Jin G, Chen Z, Zhang J, et al. Association of brain natriuretic peptide gene polymorphisms with chronic obstructive pulmonary disease complicated with pulmonary hypertension and its mechanism. Biosci Rep, 2018, 38(5): BSR20180905.
25.	Li Y, Ren W, Wang X, et al. MicroRNA-150 relieves vascular remodeling and fibrosis in hypoxia-induced pulmonary hypertension. Biomed Pharmacother, 2018, 109: 1740-1749.
26.	Ikeda KT, Hale PT, Pauciulo MW, et al. Hypoxia-induced pulmonary hypertension in different mouse strains--relation to transcriptome. Am J Respir Cell Mol Biol, 2019, 6(3): 298-309.
27.	Sheikh AY, Chun HJ, Glassford AJ, et al. In vivo genetic profling and cellular localization of apelin reveals a hypoxia-sensitive, endothelialcentered pathway activated in ischemic heart failure. Am J Physiol Heart Circ Physiol, 2007, 294(1): H88-H98.
28.	Chandra SM, Razavi H, Kim J, et al. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2011, 31(4): 814-820.
29.	Soon E, Southwood M, Sheares K, et al. Better off blue: BMPR-2 mutation, arteriovenous malformation, and pulmonary arterial hypertension. Am J Respir Crit Care Med, 2014, 189(11): 1435-1436.
30.	Braam EA, Quanjel MJ, Van Haren-Willems JH, et al. Extensive pulmonary sarcoid reaction in a patient with BMPR-2 associated idiopathic pulmonary arterial hypertension. Sarcoidosis Vasc Difuse Lung Dis, 2016, 33(2): 182-185.
31.	Nadeau V, Bonnet S, Paulin R. Letter by Nadeau et al Regarding Article, "Bmpr2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension". Circulation, 2019, 140(7): e286-e287.
32.	Alastalo TP, Li M, Perez Vde J, et al. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest, 2011, 121(9): 3735-3746.
33.	D’Amico RW, Faley S, Shim HN, et al. Pulmonary vascular platform models the efects of fow and pressure on endothelial dysfunction in BMPR2 associated pulmonary arterial hypertension. Int J Mol Sci, 2018, 19(9): 2561.
34.	Ozkan M, Dweik RA, Laskowski D, et al. High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung, 2001, 179(4): 233-243.
35.	Albarran-Juarez J, Iring A, Wang S, et al. Ofermanns S (2018) Piezo1 and Gq/G11 promote endothelial infammation depending on fow pattern and integrin activation. Exp Med, 2018, 215(10): 2655-2672.
36.	McLean DL, Kim J, Kang Y, et al. Apelin/APJ signaling is a critical regulator of statin efects in vascular endothelial cells--brief report. Arterioscler Thromb Vasc Biol, 2012, 32(11): 2640-2643.
37.	Wang X, Wu Z, He Y, et al. Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2. Mol Immunol, 2018, 101: 245-250.
38.	Young A, Wu W, Sun W, et al. Flow activation of AMP-activated protein kinase in vascular endothelium leads to Krüppel-like factor 2 expression. Arterioscler Thromb Vasc Biol, 2009, 29(11): 1902-1908.
39.	Zippel N, Loot AE, Stingl H, et al. Endothelial AMP-Activated Kinase α1 Phosphorylates eNOS on Thr495 and Decreases Endothelial NO Formation. Int J Mol Sci, 2018, 19(9): 2753.
40.	He L, Zhou Q, Huang Z, et al. PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions. J Cell Physiol, 2019, 234(6): 8668-8682.
41.	Kim J, Kang Y, Kojima Y, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med, 2013, 19(1): 74-82.
42.	Cheng J, Luo X, Huang Z, et al. Apelin/APJ system: a potential therapeutic target for endothelial dysfunction-related diseases. J Cell Physiol, 2019, 234(8): 12149-12160.
43.	Kurowska P, Barbe A, Różycka M, et al. Apelin in reproductive physiology and pathology of different species: a critical review. Int J Endocrinol, 2018, 2018: 9170480.
44.	Bertrand C, Pradère JP, Geoffre N, et al. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism. Endocrine, 2018, 60(1): 112-121.
45.	Ge YY, Li Y, Chen Q, et al. Adipokine apelin ameliorates chronic colitis in Il-10^−/− mice by promoting intestinal lymphatic functions. Biochem Pharmacol, 2018, 148: 202-212.
46.	Vafaee F. Using multi-objective optimization to identify dynamical network biomarkers as early-warning signals of complex diseases. Sci Rep, 2016, 6: 22023.
47.	Augustin HG, Koh GY. Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science, 2017, 357(6353): eaal2379.
48.	Antushevich H, Wójcik M. Review: apelin in disease. Clin Chim Acta, 2018, 483: 241-248.
49.	Zhao H, Tian XT, He LJ, et al. Apj⁺ vessels drive tumor growth and represent a tractable therapeutic target. Cell Rep, 2018, 25(5): 1241-1254.
50.	Rayalam S, Della-Fera MA, Kasser T, et al. Emerging role of apelin as a therapeutic target in cancer: a patent review. Recent Pat Anticancer Drug Discov, 2011, 6(3): 367-372.
51.	Lv D, Li L, Lu Q, et al. PAK1-coflin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13. Clin Exp Pharmacol Physiol, 2016, 43(5): 569-579.
52.	Yang L, Su T, Lv D, et al. ERK1/2 mediates lung adenocarcinoma cell proliferation and autophagy induced by apelin-13. Acta Biochim Biophys Sin (Shanghai), 2014, 46(2): 100-111.
53.	Berta J, Kenessey I, Dobos J, et al. Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis. Thorac Oncol, 2016, 5(8): 1120-1129.
54.	Ermin S, Cok G, Veral A, et al. The role of apelin in the assessment of response to chemotherapy and prognosis in stage 4 non small cell lung cancer. Turk J Med Sci, 2016, 46(5): 1353-1359.
55.	Yang S, Chen X, Pan Y, et al. Proteins associated with EGFR-TKIs resistance in patients with non-small cell lung cancer revealed by mass spectrometry. Mol Med Rep, 2016, 14(5): 4823-4829.
56.	Jang I, Jeon BT, Jeong EA, et al. Pak1/LIMK1/coflin pathway contributes to tumor migration and invasion in human non-small cell lung carcinomas and cell lines. Korean J Physiol Pharmacol, 2013, 16(3): 159-165.
57.	Machura E, Ziora K, Ziora D, et al. Serum apelin-12 level is elevated in schoolchildren with atopic asthma. Respir Med, 2013, 107(2): 196-201.
58.	Huang Z, He L, Chen Z, et al. Targeting drugs to APJ receptor: from signaling to pathophysiological effects. Cell Physiol, 2018, 234(1): 61-74.
59.	Yamazaki S, Sekiguchi A, Uchiyama A, et al. Apelin/APJ signaling suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model. Sci Rep, 2020, 10(1): 1349.
60.	Yang P, Read C, Kuc RE, et al. A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension. Br J Pharmacol, 2019, 176(9): 1206-1221.
61.	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(4): 834-840.
62.	Iturrioz X, Alvear-Perez R, De Mota N, et al. Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J, 2010, 24(5): 1506-1517.
63.	Margathe JF, Iturrioz X, Alvear-Perez R, et al. Structure-activity relationship studies toward the discovery of selective apelin receptor agonists. Med Chem, 2014, 57(7): 2908-2919.
64.	Zhou N, Fang J, Acheampong E, et al. Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1. Virology, 2003, 312(1): 196-203.
65.	Lee DK, Saldivia VR, Nguyen T, et al. Modification of the terminal residue of apelin-13 antagonizes its hypotensive action. Endocrinology, 2016, 146(1): 231-236.
66.	Zhou L, Sun H, Cheng R, et al. ELABELA, as a potential diagnostic biomarker of preeclampsia, regulates abnormally shallow placentation via APJ. Am J Physiol Endocrinol Metab, 2019, 316(5): E773-E781.
67.	Gao LR, Zhang NK, Zhang Y, et al. Overexpression of apelin in Wharton' jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats. Stem Cell Res Ther, 2018, 9(1): 6.

1. 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): 355-360.
2. 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): 471-476.
3. Medhurst AD, Jennings CA, Robbins MJ, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. Neurochem, 2019, 84(5): 1162-1172.
4. Cano Martinez LJ, Coral Vazquez RM, Mendez JP, et al. Canto P Serum concentrations of apelin-17 isoform vary in accordance to blood pressure categories in individuals with obesity class 3. Clin Exp Hypertens, 2019, 41(2): 168-173.
5. Zhou Q, Xu J, Liu M, et al. Warburg effect is involved inapelin13 induced human aorticvascular smooth muscle cells proliferation. Cell Physiol, 2019, 27(10): 921-932.
6. Xie F, Liu W, Feng F, et al. Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy. Acta Biochim Biophys Sin, 2019, 47(12): 969-980.
7. Liu MQ, Chen Z, Chen LX, et al. Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases. Acta Pharmacol Sin, 2016, 37(4): 425-443.
8. Zhang H, Chen S, Zeng M, et al. Apelin-13 administration protects against LPS induced acute lung injury by inhibiting NF-kappaB pathway and NLRP3 infammasome activation. Cell Physiol Biochem, 2018, 49(5): 1918-1932.
9. Liu M, Li H, Zhou Q, et al. ROS-Autophagy pathway mediates monocytes-human umbilical vein endothelial cells adhesion induced by apelin-13. Cell Physiol, 2019, 233(10): 6839-6850.
10. Ureche C, Tapoi L, Volovat S, et al. Cardioprotective apelin efects and the cardiac-renal axis: review of existing science and potential therapeutic applications of synthetic and native regulated apelin. Hum Hypertens, 2019, 62(5): 962-972.
11. Besserer-Offroy É, Bérubé P, Côté J, et al. The hypotensive effect of activated apelin receptor is correlated with β-arrestin recruitment. Pharmacol Res, 2018, 131: 7-16.
12. Furuya M, Okuda M, Usui H, et al. Expression of angiotensin Ⅱ receptor-like 1 in the placentas of pregnancy induced hypertension. Int J Gynecol Pathol, 2012, 31(3): 227-235.
13. Najafpour H, Soltani Hekmat A, Nekooian AA, et al. 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(1-3): 43-50.
14. Zhou Q, Chen L, Tang M, et al. Apelin/APJ system: a novel promising target for anti-aging intervention. Clin Chim Acta, 2018, 487: 233-240.
15. Vinel C, Lukjanenko L, Batut A, et al. The exerkine apelin reverses age-associated sarcopenia. Nat Med, 2018, 24(9): 1360-1371.
16. Ji W, Shi H, Shen H, et al. Mechanism of KLF4 protection against acute liver injury via inhibition of apelin signaling. Oxid Med Cell Longev, 2019, 2019: 6140360.
17. Huang Z, Wu L, Chen L. Apelin/APJ system: a novel potential therapy target for kidney disease. J Cell Physiol, 2018, 233(5): 3892-3900.
18. He S, Li J, Wang J, et al. Hypoxia exposure alleviates impaired muscular metabolism, glucose tolerance, and aerobic capacity in apelin-knockout mice. FEBS Open Bio, 2019, 9(3): 498-509.
19. Kawamata Y, Habata Y, Fukusumi S, et al. Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta, 2001, 1538(2-3): 162-171.
20. Kleinz MJ, Davenport AP. Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regul Pept, 2004, 118(3): 119-125.
21. Goetze JP, Rehfeld JF, Carlsen J, et al. Apelin: anew plasma marker of cardiopulmonary disease. Regul Pept, 2006, 133(1-3): 134-138.
22. Fan XF, Xue F, Zhang YQ, et al. The Apelin-APJ axis is an endogenous counterinjury mechanism in experimental acute lung injury. Chest, 2015, 147(4): 969-978.
23. Andersen CU, Hilberg O, Mellemkjær S, et al. Apelin and pulmonary hypertension. Pulm Circ, 2011, 1(3): 334-346.
24. Jin G, Chen Z, Zhang J, et al. Association of brain natriuretic peptide gene polymorphisms with chronic obstructive pulmonary disease complicated with pulmonary hypertension and its mechanism. Biosci Rep, 2018, 38(5): BSR20180905.
25. Li Y, Ren W, Wang X, et al. MicroRNA-150 relieves vascular remodeling and fibrosis in hypoxia-induced pulmonary hypertension. Biomed Pharmacother, 2018, 109: 1740-1749.
26. Ikeda KT, Hale PT, Pauciulo MW, et al. Hypoxia-induced pulmonary hypertension in different mouse strains--relation to transcriptome. Am J Respir Cell Mol Biol, 2019, 6(3): 298-309.
27. Sheikh AY, Chun HJ, Glassford AJ, et al. In vivo genetic profling and cellular localization of apelin reveals a hypoxia-sensitive, endothelialcentered pathway activated in ischemic heart failure. Am J Physiol Heart Circ Physiol, 2007, 294(1): H88-H98.
28. Chandra SM, Razavi H, Kim J, et al. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2011, 31(4): 814-820.
29. Soon E, Southwood M, Sheares K, et al. Better off blue: BMPR-2 mutation, arteriovenous malformation, and pulmonary arterial hypertension. Am J Respir Crit Care Med, 2014, 189(11): 1435-1436.
30. Braam EA, Quanjel MJ, Van Haren-Willems JH, et al. Extensive pulmonary sarcoid reaction in a patient with BMPR-2 associated idiopathic pulmonary arterial hypertension. Sarcoidosis Vasc Difuse Lung Dis, 2016, 33(2): 182-185.
31. Nadeau V, Bonnet S, Paulin R. Letter by Nadeau et al Regarding Article, "Bmpr2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension". Circulation, 2019, 140(7): e286-e287.
32. Alastalo TP, Li M, Perez Vde J, et al. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest, 2011, 121(9): 3735-3746.
33. D’Amico RW, Faley S, Shim HN, et al. Pulmonary vascular platform models the efects of fow and pressure on endothelial dysfunction in BMPR2 associated pulmonary arterial hypertension. Int J Mol Sci, 2018, 19(9): 2561.
34. Ozkan M, Dweik RA, Laskowski D, et al. High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung, 2001, 179(4): 233-243.
35. Albarran-Juarez J, Iring A, Wang S, et al. Ofermanns S (2018) Piezo1 and Gq/G11 promote endothelial infammation depending on fow pattern and integrin activation. Exp Med, 2018, 215(10): 2655-2672.
36. McLean DL, Kim J, Kang Y, et al. Apelin/APJ signaling is a critical regulator of statin efects in vascular endothelial cells--brief report. Arterioscler Thromb Vasc Biol, 2012, 32(11): 2640-2643.
37. Wang X, Wu Z, He Y, et al. Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2. Mol Immunol, 2018, 101: 245-250.
38. Young A, Wu W, Sun W, et al. Flow activation of AMP-activated protein kinase in vascular endothelium leads to Krüppel-like factor 2 expression. Arterioscler Thromb Vasc Biol, 2009, 29(11): 1902-1908.
39. Zippel N, Loot AE, Stingl H, et al. Endothelial AMP-Activated Kinase α1 Phosphorylates eNOS on Thr495 and Decreases Endothelial NO Formation. Int J Mol Sci, 2018, 19(9): 2753.
40. He L, Zhou Q, Huang Z, et al. PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions. J Cell Physiol, 2019, 234(6): 8668-8682.
41. Kim J, Kang Y, Kojima Y, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med, 2013, 19(1): 74-82.
42. Cheng J, Luo X, Huang Z, et al. Apelin/APJ system: a potential therapeutic target for endothelial dysfunction-related diseases. J Cell Physiol, 2019, 234(8): 12149-12160.
43. Kurowska P, Barbe A, Różycka M, et al. Apelin in reproductive physiology and pathology of different species: a critical review. Int J Endocrinol, 2018, 2018: 9170480.
44. Bertrand C, Pradère JP, Geoffre N, et al. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism. Endocrine, 2018, 60(1): 112-121.
45. Ge YY, Li Y, Chen Q, et al. Adipokine apelin ameliorates chronic colitis in Il-10^−/− mice by promoting intestinal lymphatic functions. Biochem Pharmacol, 2018, 148: 202-212.
46. Vafaee F. Using multi-objective optimization to identify dynamical network biomarkers as early-warning signals of complex diseases. Sci Rep, 2016, 6: 22023.
47. Augustin HG, Koh GY. Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science, 2017, 357(6353): eaal2379.
48. Antushevich H, Wójcik M. Review: apelin in disease. Clin Chim Acta, 2018, 483: 241-248.
49. Zhao H, Tian XT, He LJ, et al. Apj⁺ vessels drive tumor growth and represent a tractable therapeutic target. Cell Rep, 2018, 25(5): 1241-1254.
50. Rayalam S, Della-Fera MA, Kasser T, et al. Emerging role of apelin as a therapeutic target in cancer: a patent review. Recent Pat Anticancer Drug Discov, 2011, 6(3): 367-372.
51. Lv D, Li L, Lu Q, et al. PAK1-coflin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13. Clin Exp Pharmacol Physiol, 2016, 43(5): 569-579.
52. Yang L, Su T, Lv D, et al. ERK1/2 mediates lung adenocarcinoma cell proliferation and autophagy induced by apelin-13. Acta Biochim Biophys Sin (Shanghai), 2014, 46(2): 100-111.
53. Berta J, Kenessey I, Dobos J, et al. Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis. Thorac Oncol, 2016, 5(8): 1120-1129.
54. Ermin S, Cok G, Veral A, et al. The role of apelin in the assessment of response to chemotherapy and prognosis in stage 4 non small cell lung cancer. Turk J Med Sci, 2016, 46(5): 1353-1359.
55. Yang S, Chen X, Pan Y, et al. Proteins associated with EGFR-TKIs resistance in patients with non-small cell lung cancer revealed by mass spectrometry. Mol Med Rep, 2016, 14(5): 4823-4829.
56. Jang I, Jeon BT, Jeong EA, et al. Pak1/LIMK1/coflin pathway contributes to tumor migration and invasion in human non-small cell lung carcinomas and cell lines. Korean J Physiol Pharmacol, 2013, 16(3): 159-165.
57. Machura E, Ziora K, Ziora D, et al. Serum apelin-12 level is elevated in schoolchildren with atopic asthma. Respir Med, 2013, 107(2): 196-201.
58. Huang Z, He L, Chen Z, et al. Targeting drugs to APJ receptor: from signaling to pathophysiological effects. Cell Physiol, 2018, 234(1): 61-74.
59. Yamazaki S, Sekiguchi A, Uchiyama A, et al. Apelin/APJ signaling suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model. Sci Rep, 2020, 10(1): 1349.
60. Yang P, Read C, Kuc RE, et al. A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension. Br J Pharmacol, 2019, 176(9): 1206-1221.
61. 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(4): 834-840.
62. Iturrioz X, Alvear-Perez R, De Mota N, et al. Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J, 2010, 24(5): 1506-1517.
63. Margathe JF, Iturrioz X, Alvear-Perez R, et al. Structure-activity relationship studies toward the discovery of selective apelin receptor agonists. Med Chem, 2014, 57(7): 2908-2919.
64. Zhou N, Fang J, Acheampong E, et al. Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1. Virology, 2003, 312(1): 196-203.
65. Lee DK, Saldivia VR, Nguyen T, et al. Modification of the terminal residue of apelin-13 antagonizes its hypotensive action. Endocrinology, 2016, 146(1): 231-236.
66. Zhou L, Sun H, Cheng R, et al. ELABELA, as a potential diagnostic biomarker of preeclampsia, regulates abnormally shallow placentation via APJ. Am J Physiol Endocrinol Metab, 2019, 316(5): E773-E781.
67. Gao LR, Zhang NK, Zhang Y, et al. Overexpression of apelin in Wharton' jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats. Stem Cell Res Ther, 2018, 9(1): 6.

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