The alamarBlue test revealed that recombinant

The alamarBlue test revealed that recombinant apelin led to an increase in basal and IGF1- and FHS-induced ovarian cell proliferation. Apelin increased ERK1/2 and Akt protein expression, but cell proliferation returned to control levels in the presence of kinase inhibitors. This suggests that the proliferative effect of apelin is due to the activation of ERK1/2 and Akt signaling pathways. Thus, a potential new mechanism of action of apelin can be described as follows: Apelin-induced stimulation of steroid secretion and cell proliferation controls ovarian folliculogenesis, oocyte loss/selection or atresia. Apelin-induced increases in the proliferation of rat granulosa cells and decreased apoptosis via the PI3/Akt signaling pathways have been recorded [42]. However, other models have yielded different results for the action of apelin on cell proliferation. In human breast cancer cells (MCF-7) [43] and lung adenocarcinoma [44] apelin-13 promoted cell proliferation via the ERK1/2 signaling pathway. Similarly, in endothelial progenitor cells [45] and retinal pigment epithelial cells [46] apelin increased cell proliferation via the IP3/Akt signaling pathway. In contrast, apelin was found to inhibit the proliferation and migration of pulmonary arterial smooth muscle cells [47].
Conflict of interest
Funding This research was supported by Jagiellonian University in Krakow DSC/MND/WBiNoZ/IZ/5/2014 and by Ministry of Science and Higher Education for the PHC project under the bilateral Polish-France Agreement “POLONIUM” (2016–2017) between Agnieszka Rak, PhD and Joelle Dupont, PhD.
Acknowledgments
Introduction Apelin is an endogenous ligand of the specific receptor APJ that belongs to the G protein-coupled receptor family [1,2]. In humans, the apelin coding sequence is localized on chromosome Xq25-q26.1, and native apelin peptide is produced through processing from the C-terminal portion of the pre-proprotein consisting of 77 amino Isochlorogenic acid C residues. During posttranslational processing of pre-proprotein, several active forms of apelin molecule consisting of 12, 13, 15, 16, 17, 19, 28, 31 or 36 amino acid residues and the pyroglutamated apelin-13 ((Pyr1)-apelin-13) are produced [3,4]. Recently, another endogenous peptide activator of the APJ receptor, Toddler/ELABELA, was found to play a crucial role in zebrafish (Danio rerio) embryonic development [5]. The 36-amino-acid apelin variant appears to be the parent peptide, and the 12-amino-acid apelin is the smallest fragment able to activate the apelin receptor. Apelin-13 and apelin-36 have different receptor binding affinities and cause different intracellular trafficking of APJ. Also, the shorter apelin isoform seems to be a more potent activator of APJ than apelin-36 [6]. APJ is a typical 380-amino-acid G protein-coupled receptor with 7 transmembrane domains showing close sequence homology to the angiotensin II receptor type 1 (30–40% amino acid sequence identity). However, when expressed in Chinese hamster ovary (CHO) cells or in fibroblasts, angiotensin II does not interact with the APJ receptor [1]. Apelin receptor is present in various parts of the body. In the central nervous system, APJ receptor has been discovered in the hypothalamus, thalamus, midbrain, reticular formation, cerebral cortex, basal ganglia, glial cells and white matter. In the gastrointestinal tract, APJ receptor expression has been found in the acinar cells of the pancreas, pancreatic duct and the islet beta-cells [7,8]. In the stomach, abundant APJ expression is observed in the fundic region, whereas in the duodenum, it is observed in the tunica mucosa, in particular, in the duodenal epithelium cells [7,8]. In the jejunum, APJ expression is noted mostly in the upper half of the villi [7,9]. In the liver, APJ is strongly expressed in the hepatocytes and hepatic stellate cells [10]. Also, APJ is found in cardiomyocytes and vascular endothelial and smooth muscle cells. In addition, apelin receptor mRNA is present in lung endothelial cells, kidneys and mammary glands [11].