DOI QR코드

DOI QR Code

Apelin-APJ Signaling: a Potential Therapeutic Target for Pulmonary Arterial Hypertension

  • Kim, Jongmin (Department of Life Systems Sookmyung Women's University)
  • Received : 2013.10.24
  • Accepted : 2013.12.02
  • Published : 2014.03.31

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by the vascular remodeling of the pulmonary arterioles, including formation of plexiform and concentric lesions comprised of proliferative vascular cells. Clinically, PAH leads to increased pulmonary arterial pressure and subsequent right ventricular failure. Existing therapies have improved the outcome but mortality still remains exceedingly high. There is emerging evidence that the seven-transmembrane G-protein coupled receptor APJ and its cognate endogenous ligand apelin are important in the maintenance of pulmonary vascular homeostasis through the targeting of critical mediators, such as Kr$\ddot{u}$ppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and microRNAs (miRNAs). Disruption of this pathway plays a major part in the pathogenesis of PAH. Given its role in the maintenance of pulmonary vascular homeostasis, the apelin-APJ pathway is a potential target for PAH therapy. This review highlights the current state in the understanding of the apelin-APJ axis related to PAH and discusses the therapeutic potential of this signaling pathway as a novel paradigm of PAH therapy.

Keywords

References

  1. Alastalo, T.P., Li, M., Perez Vde, J., Pham, D., Sawada, H., Wang, J.K., Koskenvuo, M., Wang, L., Freeman, B.A., Chang, H.Y., et al. (2011). Disruption of $PPAR\gamma$/$\beta$-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J. Clin. Invest. 121, 3735-3746. https://doi.org/10.1172/JCI43382
  2. Ashley, E.A., Powers, J., Chen, M., Kundu, R., Finsterbach, T., Caffarelli, A., Deng, A., Eichhorn, J., Mahajan, R., Agrawal, R., et al. (2005). The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc. Res. 65, 73-82. https://doi.org/10.1016/j.cardiores.2004.08.018
  3. Barst, R.J. (2005). PDGF signaling in pulmonary arterial hypertension. J. Clin. Invest. 115, 2691-2694. https://doi.org/10.1172/JCI26593
  4. Benisty, J.I., McLaughlin, V.V., Landzberg, M.J., Rich, J.D., Newburger, J.W., Rich, S., and Folkman, J. (2004). Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126, 1255-1261. https://doi.org/10.1378/chest.126.4.1255
  5. Brock, M., Samillan, V.J., Trenkmann, M., Schwarzwald, C., Ulrich, S., Gay, R.E., Gassmann, M., Ostergaard, L., Gay, S., Speich, R., et al. (2012). AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur. Heart J. doi:10.1093/eurheartj/ehs060.
  6. Budhiraja, R., Tuder, R.M., and Hassoun, P.M. (2004). Endothelial dysfunction in pulmonary hypertension. Circulation 109, 159-165. https://doi.org/10.1161/01.CIR.0000102381.57477.50
  7. Chandra, S.M., Razavi, H., Kim, J., Agrawal, R., Kundu, R.K., de Jesus Perez, V., Zamanian, R.T., Quertermous, T., and Chun, H.J. (2011). Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler. Thromb. Vasc. Biol. 31, 814-820. https://doi.org/10.1161/ATVBAHA.110.219980
  8. Chen, M.M., Ashley, E.A., Deng, D.X., Tsalenko, A., Deng, A., Tabibiazar, R., Ben-Dor, A., Fenster, B., Yang, E., King, J.Y., et al. (2003). Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108, 1432-1439. https://doi.org/10.1161/01.CIR.0000091235.94914.75
  9. Cheng, X., Cheng, X.S., and Pang, C.C. (2003). Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats. Eur. J. Pharmacol. 470, 171-175. https://doi.org/10.1016/S0014-2999(03)01821-1
  10. Chun, H.J., Ali, Z.A., Kojima, Y., Kundu, R.K., Sheikh, A.Y., Agrawal, R., Zheng, L., Leeper, N.J., Pearl, N.E., Patterson, A.J., et al. (2008). Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J. Clin. Invest. 118, 3343-3354.
  11. De Mota, N., Reaux-Le Goazigo, A., El Messari, S., Chartrel, N., Roesch, D., Dujardin, C., Kordon, C., Vaudry, H., Moos, F., and Llorens-Cortes, C. (2004). Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc. Natl. Acad. Sci. USA 101, 10464-10469. https://doi.org/10.1073/pnas.0403518101
  12. Deng, Z., Morse, J.H., Slager, S.L., Cuervo, N., Moore, K.J., Venetos, G., Kalachikov, S., Cayanis, E., Fischer, S.G., Barst, R.J., et al. (2000). Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67, 737-744. https://doi.org/10.1086/303059
  13. Falcao-Pires, I., Goncalves, N., Henriques-Coelho, T., Moreira-Goncalves, D., Roncon-Albuquerque, R. Jr., and Leite-Moreira, A.F. (2009). Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension. Am. J. Physiol. Heart Circ. Physiol. 296, H2007-H2014. https://doi.org/10.1152/ajpheart.00089.2009
  14. Ghofrani, H.A., Morrell, N.W., Hoeper, M.M., Olschewski, H., Peacock, A.J., Barst, R.J., Shapiro, S., Golpon, H., Toshner, M., Grimminger, F., et al. (2010). Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med. 182, 1171-1177. https://doi.org/10.1164/rccm.201001-0123OC
  15. Giaid, A., and Saleh, D. (1995). Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 333, 214-221. https://doi.org/10.1056/NEJM199507273330403
  16. Goetze, J.P., Rehfeld, J.F., Carlsen, J., Videbaek, R., Andersen, C. B., Boesgaard, S., and Friis-Hansen, L. (2006). Apelin: a new plasma marker of cardiopulmonary disease. Regul. Pept. 133, 134-138. https://doi.org/10.1016/j.regpep.2005.09.032
  17. Hamid, R., Cogan, J.D., Hedges, L.K., Austin, E., Phillips, J.A. 3rd, Newman, J.H., and Loyd, J.E. (2009). Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum. Mutat. 30, 649-654. https://doi.org/10.1002/humu.20922
  18. Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57-70. https://doi.org/10.1016/S0092-8674(00)81683-9
  19. Hansmann, G., Wagner, R.A., Schellong, S., Perez, V.A., Urashima, T., Wang, L., Sheikh, A.Y., Suen, R.S., Stewart, D.J., and Rabinovitch, M. (2007). Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferatoractivated receptor-gamma activation. Circulation 115, 1275-1284.
  20. Hosoya, M., Kawamata, Y., Fukusumi, S., Fujii, R., Habata, Y., Hinuma, S., Kitada, C., Honda, S., Kurokawa, T., Onda, H., et al. (2000). Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J. Biol. Chem. 275, 21061-21067. https://doi.org/10.1074/jbc.M908417199
  21. Humbert, M., Sitbon, O., Chaouat, A., Bertocchi, M., Habib, G., Gressin, V., Yaici, A., Weitzenblum, E., Cordier, J.F., Chabot, F., et al. (2010). Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122, 156-163. https://doi.org/10.1161/CIRCULATIONAHA.109.911818
  22. Ishida, J., Hashimoto, T., Hashimoto, Y., Nishiwaki, S., Iguchi, T., Harada, S., Sugaya, T., Matsuzaki, H., Yamamoto, R., Shiota, N., et al. (2004). Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J. Biol. Chem. 279, 26274-26279. https://doi.org/10.1074/jbc.M404149200
  23. Iwanaga, Y., Kihara, Y., Takenaka, H., and Kita, T. (2006). Downregulation of cardiac apelin system in hypertrophied and failing hearts: Possible role of angiotensin II-angiotensin type 1 receptor system. J. Mol. Cell Cardiol. 41, 798-806. https://doi.org/10.1016/j.yjmcc.2006.07.004
  24. Izikki, M., Guignabert, C., Fadel, E., Humbert, M., Tu, L., Zadigue, P., Dartevelle, P., Simonneau, G., Adnot, S., Maitre, B., et al. (2009). Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J. Clin. Invest. 119, 512-523. https://doi.org/10.1172/JCI35070
  25. Kaneko, F.T., Arroliga, A.C., Dweik, R.A., Comhair, S.A., Laskowski, D., Oppedisano, R., Thomassen, M.J., and Erzurum, S.C. (1998). Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 158, 917-923. https://doi.org/10.1164/ajrccm.158.3.9802066
  26. Kang, Y., Kim, J., Anderson, J.P., Wu, J., Gleim, S.R., Kundu, R.K., McLean, D.L., Kim, J.D., Park, H., Jin, S.W., et al. (2013). Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development. Circ. Res. 113, 22-31. https://doi.org/10.1161/CIRCRESAHA.113.301324
  27. Kawamata, Y., Habata, Y., Fukusumi, S., Hosoya, M., Fujii, R., Hinuma, S., Nishizawa, N., Kitada, C., Onda, H., Nishimura, O., et al. (2001). Molecular properties of apelin: tissue distribution and receptor binding. Biochim. Biophys. Acta 1538, 162-171. https://doi.org/10.1016/S0167-4889(00)00143-9
  28. Kim, V.N. (2005). Small RNAs: classification, biogenesis, and function. Mol. Cells 19, 1-15. https://doi.org/10.1016/j.molcel.2005.05.026
  29. Kim, Y., and Kim, V.N. (2012). MicroRNA factory: RISC assembly from precursor microRNAs. Mol. Cell 46, 384-386. https://doi.org/10.1016/j.molcel.2012.05.012
  30. Kim, J., Kang, Y., Kojima, Y., Lighthouse, J.K., Hu, X., Aldred, M.A., McLean, D.L., Park, H., Comhair, S.A., Greif, D.M., et al. (2013). An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat. Med. 19, 74-82. https://doi.org/10.1038/nm.3040
  31. Lee, D.K., Cheng, R., Nguyen, T., Fan, T., Kariyawasam, A.P., Liu, Y., Osmond, D.H., George, S.R., and O'Dowd, B.F. (2000). Characterization of apelin, the ligand for the APJ receptor. J. Neurochem. 74, 34-41.
  32. Lin, Z., Kumar, A., SenBanerjee, S., Staniszewski, K., Parmar, K., Vaughan, D.E., Gimbrone, M.A. Jr., Balasubramanian, V., Garcia-Cardena, G., and Jain, M.K. (2005). Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ. Res. 96, e48-e57. https://doi.org/10.1161/01.RES.0000159707.05637.a1
  33. Machado, R.D., Eickelberg, O., Elliott, C.G., Geraci, M.W., Hanaoka, M., Loyd, J.E., Newman, J.H., Phillips, J.A. 3rd., Soubrier, F., Trembath, R.C., et al. (2009). Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S32-S42. https://doi.org/10.1016/j.jacc.2009.04.015
  34. Masri, F.A., Xu, W., Comhair, S.A., Asosingh, K., Koo, M., Vasanji, A., Drazba, J., Anand-Apte, B., and Erzurum, S.C. (2007). Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 293, L548-L554. https://doi.org/10.1152/ajplung.00428.2006
  35. McLaughlin, V.V., and McGoon, M.D. (2006). Pulmonary arterial hypertension. Circulation 114, 1417-1431. https://doi.org/10.1161/CIRCULATIONAHA.104.503540
  36. McLean, D.L., Kim, J., Kang, Y., Shi, H., Atkins, G.B., Jain, M.K., and Chun, H.J. (2012). Apelin/APJ signaling is a critical regulator of statin effects in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 32, 2640-2643. https://doi.org/10.1161/ATVBAHA.112.300317
  37. Medhurst, A.D., Jennings, C.A., Robbins, M.J., Davis, R.P., Ellis, C., Winborn, K.Y., Lawrie, K.W., Hervieu, G., Riley, G., Bolaky, J.E., et al. (2003). Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J. Neurochem. 84, 1162-1172. https://doi.org/10.1046/j.1471-4159.2003.01587.x
  38. Moncada, S., and Higgs, E.A. (2006). The discovery of nitric oxide and its role in vascular biology. Br. J. Pharmacol. 147 Suppl 1, S193-S201.
  39. O'Carroll, A.M., Lolait, S.J., and Howell, G.M. (2006). Transcriptional regulation of the rat apelin receptor gene: promoter cloning and identification of an Sp1 site necessary for promoter activity. J. Mol. Endocrinol. 36, 221-235. https://doi.org/10.1677/jme.1.01927
  40. O'Dowd, B.F., Heiber, M., Chan, A., Heng, H.H., Tsui, L.C., Kennedy, J.L., Shi, X., Petronis, A., George, S.R., and Nguyen, T. (1993). A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136, 355-360. https://doi.org/10.1016/0378-1119(93)90495-O
  41. Ozkan, M., Dweik, R.A., Laskowski, D., Arroliga, A.C., and Erzurum, S.C. (2001). High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung 179, 233-243. https://doi.org/10.1007/s004080000064
  42. Parikh, V.N., Jin, R.C., Rabello, S., Gulbahce, N., White, K., Hale, A., Cottrill, K.A., Shaik, R.S., Waxman, A.B., Zhang, Y.Y., et al. (2012). MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation 125, 1520-1532. https://doi.org/10.1161/CIRCULATIONAHA.111.060269
  43. Pullamsetti, S.S., Doebele, C., Fischer, A., Savai, R., Kojonazarov, B., Dahal, B.K., Ghofrani, H.A., Weissmann, N., Grimminger, F., Bonauer, A., et al. (2012). Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 185, 409-419. https://doi.org/10.1164/rccm.201106-1093OC
  44. Rabinovitch, M. (2007). Pathobiology of pulmonary hypertension. Annu. Rev. Pathol. 2, 369-399. https://doi.org/10.1146/annurev.pathol.2.010506.092033
  45. Rai, P.R., Cool, C.D., King, J.A., Stevens, T., Burns, N., Winn, R.A., Kasper, M., and Voelkel, N.F. (2008). The cancer paradigm of severe pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 178, 558-564. https://doi.org/10.1164/rccm.200709-1369PP
  46. Raja, S.G. (2010). Endothelin receptor antagonists for pulmonary arterial hypertension: an overview. Cardiovasc. Ther. 28, e65-e71. https://doi.org/10.1111/j.1755-5922.2010.00158.x
  47. Roberts, K.E., McElroy, J.J., Wong, W.P., Yen, E., Widlitz, A., Barst, R.J., Knowles, J.A., and Morse, J.H. (2004). BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur. Respir. J. 24, 371-374. https://doi.org/10.1183/09031936.04.00018604
  48. Rubin, L.J. (1997). Primary pulmonary hypertension. N. Engl. J. Med. 336, 111-117. https://doi.org/10.1056/NEJM199701093360207
  49. Sakao, S., Tatsumi, K., and Voelkel, N.F. (2010). Reversible or irreversible remodeling in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 43, 629-634. https://doi.org/10.1165/rcmb.2009-0389TR
  50. Sen-Banerjee, S., Mir, S., Lin, Z., Hamik, A., Atkins, G.B., Das, H., Banerjee, P., Kumar, A., and Jain, M.K. (2005). Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 112, 720-726. https://doi.org/10.1161/CIRCULATIONAHA.104.525774
  51. Sheikh, A.Y., Chun, H.J., Glassford, A.J., Kundu, R.K., Kutschka, I., Ardigo, D., Hendry, S.L., Wagner, R.A., Chen, M.M., Ali, Z.A., et al. (2008). In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure. Am. J. Physiol. Heart Circ. Physiol. 294, H88-H98. https://doi.org/10.1152/ajpheart.00935.2007
  52. Simonneau, G., Robbins, I.M., Beghetti, M., Channick, R.N., Delcroix, M., Denton, C.P., Elliott, C.G., Gaine, S.P., Gladwin, M.T., Jing, Z.C., et al. (2009). Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S43-S54. https://doi.org/10.1016/j.jacc.2009.04.012
  53. Szokodi, I., Tavi, P., Foldes, G., Voutilainen-Myllyla, S., Ilves, M., Tokola, H., Pikkarainen, S., Piuhola, J., Rysa, J., Toth, M., et al. (2002). Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ. Res. 91, 434-440. https://doi.org/10.1161/01.RES.0000033522.37861.69
  54. Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kakegawa, T., Zou, M.X., Kawamata, Y., Fukusumi, S., Hinuma, S., Kitada, C., et al. (1998). Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251, 471-476. https://doi.org/10.1006/bbrc.1998.9489
  55. Tatemoto, K., Takayama, K., Zou, M.X., Kumaki, I., Zhang, W., Kumano, K., and Fujimiya, M. (2001). The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul. Pept. 99, 87-92. https://doi.org/10.1016/S0167-0115(01)00236-1
  56. Tuder, R.M., Groves, B., Badesch, D.B., and Voelkel, N.F. (1994). Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275-285.
  57. Tuder, R.M., Cool, C.D., Yeager, M., Taraseviciene-Stewart, L., Bull, T.M., and Voelkel, N.F. (2001). The pathobiology of pulmonary hypertension. Endothelium Clin. Chest Med. 22, 405-418. https://doi.org/10.1016/S0272-5231(05)70280-X
  58. Urbich, C., Kuehbacher, A., and Dimmeler, S. (2008). Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc. Res. 79, 581-588. https://doi.org/10.1093/cvr/cvn156
  59. Zaidi, S.H., You, X.M., Ciura, S., Husain, M., and Rabinovitch, M. (2002). Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105, 516-521. https://doi.org/10.1161/hc0402.102866
  60. Zamanian, R.T., Hansmann, G., Snook, S., Lilienfeld, D., Rappaport, K.M., Reaven, G.M., Rabinovitch, M., and Doyle, R.L. (2009). Insulin resistance in pulmonary arterial hypertension. Eur. Respir. J. 33, 318-324.

Cited by

  1. Negative regulation of NOD1 mediated angiogenesis by PPARγ-regulated miR-125a vol.482, pp.1, 2017, https://doi.org/10.1016/j.bbrc.2016.11.032
  2. A PPARγ-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-02852-4
  3. Advances in treatment of pulmonary arterial hypertension: patent review vol.27, pp.8, 2017, https://doi.org/10.1080/13543776.2017.1313232
  4. MicroRNAs in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment vol.9, pp.3, 2015, https://doi.org/10.1016/j.jash.2014.12.011
  5. Update in treatment options in pulmonary hypertension vol.35, pp.6, 2016, https://doi.org/10.1016/j.healun.2016.01.020
  6. Microglia-Induced Maladaptive Plasticity Can Be Modulated by NeuropeptidesIn Vivo vol.2015, 2015, https://doi.org/10.1155/2015/135342
  7. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension vol.47, pp.7, 2015, https://doi.org/10.1038/emm.2015.45
  8. Reversal of MicroRNA Dysregulation in an Animal Model of Pulmonary Hypertension vol.11, pp.1, 2016, https://doi.org/10.1371/journal.pone.0147827
  9. New targets for pulmonary arterial hypertension vol.23, pp.5, 2017, https://doi.org/10.1097/MCP.0000000000000404
  10. Scutellarin attenuates vasospasm through the Erk5-KLF2-eNOS pathway after subarachnoid hemorrhage in rats vol.34, 2016, https://doi.org/10.1016/j.jocn.2016.09.028
  11. Advances in Therapeutic Interventions for Patients With Pulmonary Arterial Hypertension vol.130, pp.24, 2014, https://doi.org/10.1161/CIRCULATIONAHA.114.006974
  12. Endothelial miR-26a regulates VEGF-Nogo-B receptor-mediated angiogenesis vol.50, pp.7, 2017, https://doi.org/10.5483/BMBRep.2017.50.7.085
  13. Emerging role of angiogenesis in adaptive and maladaptive right ventricular remodeling in pulmonary hypertension vol.314, pp.3, 2018, https://doi.org/10.1152/ajplung.00374.2017
  14. Epigenetic Regulation and Its Therapeutic Potential in Pulmonary Hypertension vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.00241
  15. GPCRs in pulmonary arterial hypertension: tipping the balance vol.175, pp.15, 2018, https://doi.org/10.1111/bph.14172
  16. Targeting drugs to APJ receptor: From signaling to pathophysiological effects vol.234, pp.1, 2018, https://doi.org/10.1002/jcp.27047
  17. Acute inhalation of ozone induces DNA methylation of apelin in lungs of Long-Evans rats vol.30, pp.4-5, 2018, https://doi.org/10.1080/08958378.2018.1483984
  18. Emerging therapeutics in pulmonary hypertension vol.314, pp.5, 2018, https://doi.org/10.1152/ajplung.00259.2017
  19. The Search for Disease-Modifying Therapies in Pulmonary Hypertension pp.1940-4034, 2019, https://doi.org/10.1177/1074248419829172
  20. Therapeutic implications of microRNAs in pulmonary arterial hypertension vol.47, pp.6, 2014, https://doi.org/10.5483/bmbrep.2014.47.6.085
  21. LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT 1 R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension vol.19, pp.None, 2014, https://doi.org/10.1186/s12931-018-0956-z
  22. The Role of G Protein-Coupled Receptors in the Right Ventricle in Pulmonary Hypertension vol.5, pp.None, 2014, https://doi.org/10.3389/fcvm.2018.00179
  23. A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects vol.61, pp.6, 2014, https://doi.org/10.1021/acs.jmedchem.7b01353
  24. International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand vol.71, pp.4, 2014, https://doi.org/10.1124/pr.119.017533
  25. The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders vol.1455, pp.1, 2019, https://doi.org/10.1111/nyas.14123
  26. Current Treatment Strategies and Nanoparticle-Mediated Drug Delivery Systems for Pulmonary Arterial Hypertension vol.20, pp.23, 2014, https://doi.org/10.3390/ijms20235885
  27. Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury vol.25, pp.6, 2014, https://doi.org/10.1016/j.stem.2019.10.006
  28. Elabela: A Novel Biomarker for Right Ventricular Pressure Overload in Children With Pulmonary Stenosis or Pulmonary Atresia With Intact Ventricular Septum vol.7, pp.None, 2014, https://doi.org/10.3389/fcvm.2020.581848
  29. Activation of the IL-1β/KLF2/HSPH1 pathway promotes STAT3 phosphorylation in alveolar macrophages during LPS-induced acute lung injury vol.40, pp.3, 2014, https://doi.org/10.1042/bsr20193572
  30. Targeted Drugs for Treatment of Pulmonary Arterial Hypertension: Past, Present, and Future Perspectives vol.63, pp.24, 2014, https://doi.org/10.1021/acs.jmedchem.0c01093
  31. Current and future treatments of pulmonary arterial hypertension vol.178, pp.1, 2021, https://doi.org/10.1111/bph.15016
  32. Apelin pathway in cardiovascular, kidney, and metabolic diseases: Therapeutic role of apelin analogs and apelin receptor agonists vol.147, pp.None, 2014, https://doi.org/10.1016/j.peptides.2021.170697