Alternative titles; symbols
HGNC Approved Gene Symbol: APLN
Cytogenetic location: Xq26.1 Genomic coordinates (GRCh38) : X:129,645,259-129,654,956 (from NCBI)
Apelin is a neuropeptide expressed in the supraoptic and paraventricular nuclei that acts on specific receptors located on vasopressinergic neurons (De Mota et al., 2004).
Tatemoto et al. (1998) purified a protein that bound to the APJ receptor (600052). Based on peptide sequences, they cloned the corresponding human cDNA. The gene encodes a 77-amino acid polypeptide that includes a secretory signal sequence. Synthetic 36-amino acid apelin (apelin-36), corresponding to the most C-terminal 36 residues of preproapelin, caused the acidification of cells expressing transfected APJ, but not other receptors. The authors stated that apelin is an endogenous ligand for the APJ receptor.
By RT-PCR analysis, Habata et al. (1999) detected highest levels of apelin in lactating rat mammary glands. Bioassays with human APJ-expressing CHO cells confirmed the presence of active apelin in rat mammary gland, rat milk, and at variable levels in bovine milk, with highest concentrations in colostrum.
Cayabyab et al. (2000) reported that in addition to the chemokine receptors CCR5 (601373) and CXCR4 (162643), primary HIV-1 isolates can also use APJ as a coreceptor. CAT reporter assays showed that apelin-36 or apelin-15, but not apelin-13, inhibited HIV-1 entry into CD4 (186940)-APJ-expressing cells, suggesting that the anti-HIV-1 activity of apelin is separate from its acidification activity. Peptide mapping analysis determined that apelin residues 63 through 75 appear to be essential for antiviral activity.
Using cDNA microarray analysis on paired samples of left ventricle obtained before and after placement of a left ventricular assist device in 11 patients, Chen et al. (2003) found that APJ was the most significantly upregulated gene. Using immunoassay and immunohistochemical techniques, they demonstrated that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading. The authors also demonstrated increases in the plasma level of apelin in patients with left ventricular dysfunction. Chen et al. (2003) concluded that their findings indicate an important apelin-APJ paracrine signaling pathway in the heart.
De Mota et al. (2004) investigated whether apelin interacts with arginine vasopressin (AVP; 192340) to maintain body fluid homeostasis. They characterized the predominant molecular forms of endogenous hypothalamic and plasma apelin as corresponding to apelin-13 and, to a lesser extent, to apelin-17. They then demonstrated that, in lactating rats, apelin was colocalized with AVP in supraoptic nucleus magnocellular neurons and, when given intracerebroventricularly, inhibited the phasic electrical activity of AVP neurons. Various observations from other experiments demonstrated that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. The coexistence of apelin and AVP in magnocellular neurons, their opposite biologic effects, and regulation are likely to play a key role in maintaining body fluid homeostasis.
Tatemoto et al. (2001) detected apelin-like immunoreactivity within the endothelium of small arteries in Wistar rats. Apelin peptides significantly lowered arterial blood pressure and transiently elevated plasma nitrite/nitrate levels; these effects were abolished by the presence of a nitric oxide synthase inhibitor. Tatemoto et al. (2001) concluded that apelin might lower blood pressure through a nitric oxide-dependent mechanism.
Szokodi et al. (2002) infused apelin into isolated perfused rat hearts and observed a dose-dependent positive inotropic effect (EC50, 33 pmol/L). Moreover, the preload-induced increase in dP/dt(max) was significantly augmented (p less than 0.05) in the presence of apelin. Szokodi et al. (2002) concluded that apelin is one of the most potent endogenous positive inotropic substances yet identified.
Scimia et al. (2012) reported that genetic loss of APJ, a G protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin, the endogenous APJ ligand, remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate G-alpha-i (see 139310) and elicits a protective response, stretch signals in an APJ-dependent, G protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of beta-arrestins (e.g., 107940) or by pharmacologic doses of apelin acting through G-alpha-i. Scimia et al. (2012) concluded that, taken together, their data indicated that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.
Scott (2001) mapped the apelin gene to Xq25-q26.3 based on sequence similarity between the apelin sequence and a chromosome X PAC clone (GenBank AL022162).
Cayabyab, M., Hinuma, S., Farzan, M., Choe, H., Fukusumi, S., Kitada, C., Nishizawa, N., Hosoya, M., Nishimura, O., Messele, T., Pollakis, G., Goudsmit, J., Fujino, M., Sodroski, J. Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ, inhibits human immunodeficiency virus type 1 entry. J. Virol. 74: 11972-11976, 2000. [PubMed: 11090199] [Full Text: https://doi.org/10.1128/jvi.74.24.11972-11976.2000]
Chen, M. M., Ashley, E. A., Deng, D. X. F., Tsalenko, A., Deng, A., Tabibiazar, R., Ben-Dor, A., Fenster, B., Yang, E., King, J. Y., Fowler, M., Robbins, R., Johnson, F. L., Bruhn, L., McDonagh, T., Dargie, H., Yakhini, Z., Tsao, P. S., Quertermous, T. Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108: 1432-1439, 2003. [PubMed: 12963638] [Full Text: https://doi.org/10.1161/01.CIR.0000091235.94914.75]
De Mota, N., Reaux-Le Goazigo, A., El Messari, S., Chartrel, N., Roesch, D., Dujardin, C., Kordon, C., Vaudry, H., Moos, F., Llorens-Cortes, C. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc. Nat. Acad. Sci. 101: 10464-10469, 2004. [PubMed: 15231996] [Full Text: https://doi.org/10.1073/pnas.0403518101]
Habata, Y., Fujii, R., Hosoya, M., Fukusumi, S., Kawamata, Y., Hinuma, S., Kitada, C., Nishizawa, N., Murosaki, S., Kurokawa, T., Onda, H., Tatemoto, K., Fujino, M. Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim. Biophys. Acta 1452: 25-35, 1999. [PubMed: 10525157] [Full Text: https://doi.org/10.1016/s0167-4889(99)00114-7]
Scimia, M. C., Hurtado, C., Ray, S., Metzler, S., Wei, K., Wang, J., Woods, C. E., Purcell, N. H., Catalucci, D., Akasaka, T., Bueno, O. F., Vlasuk, G. P., Kaliman, P., Bodmer, R., Smith, L. H., Ashley, E., Mercola, M., Brown, J. H., Ruiz-Lozano, P. APJ acts as a dual receptor in cardiac hypertrophy. Nature 488: 394-398, 2012. [PubMed: 22810587] [Full Text: https://doi.org/10.1038/nature11263]
Scott, A. F. Personal Communication. Baltimore, Md. 2/7/2001.
Szokodi, I., Tavi, P., Foldes, G., Voutilainen-Myllyla, S., Ilves, M., Tokola, H., Pikkarainen, S., Piuhola, J., Rysa, J., Toth, M., Ruskoaho, H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ. Res. 91: 434-440, 2002. [PubMed: 12215493] [Full Text: https://doi.org/10.1161/01.res.0000033522.37861.69]
Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kakegawa, T., Zou, M.-X., Kawamata, Y., Fukusumi, S., Hinuma, S., Kitada, C., Kurokawa, T., Onda, H., Fujino, M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251: 471-476, 1998. [PubMed: 9792798] [Full Text: https://doi.org/10.1006/bbrc.1998.9489]
Tatemoto, K., Takayama, K., Zou, M.-X., Kumaki, I., Zhang, W., Kumano, K., Fujimiya, M. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul. Pept. 99: 87-92, 2001. [PubMed: 11384769] [Full Text: https://doi.org/10.1016/s0167-0115(01)00236-1]