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Current Drug Targets 2022Elabela, a bioactive micropeptide, is recognized as the second endogenous ligand for the Apelin receptor and is widely distributed in different tissues and organs.... (Review)
Review
Elabela, a bioactive micropeptide, is recognized as the second endogenous ligand for the Apelin receptor and is widely distributed in different tissues and organs. Elabela plays an important role in various physiological processes, such as blood pressure control, heart morphogenesis, apoptosis, angiogenesis, cell proliferation, migration, etc. Elabela is also implicated in pathological conditions, like cardiac dysfunctions, heart failure, hypertension, kidney diseases, cancer and CNS disorders. The association of Elabela with these disease conditions makes it a potential target for their therapy. This review summarizes the physiological role of Elabela peptide as well as its implication in various disease conditions.
Topics: Humans; Apelin; Peptide Hormones; Apelin Receptors; Hypertension; Heart Failure
PubMed: 36029072
DOI: 10.2174/1389450123666220826160123 -
Life Sciences Sep 2023The apelin receptor (APJ) and the opioid-related nociceptin receptor 1 (ORL1) are family A G protein-coupled receptors that participate in a variety of physiological...
The apelin receptor (APJ) and the opioid-related nociceptin receptor 1 (ORL1) are family A G protein-coupled receptors that participate in a variety of physiological processes. The distribution and function of APJ and ORL1 in the nervous system and peripheral tissues are similar; however, the detailed mechanism of how these two receptors modulate signaling and physiological effects remains unclear. Here, we examined whether APJ and ORL1 form dimers, and investigated signal transduction pathways. The endogenous co-expression of APJ and ORL1 in SH-SY5Y cells was confirmed by western blotting and RT-PCR. Bioluminescence and fluorescence resonance energy transfer assays, as well as a proximity ligation assay and co-immunoprecipitation experiments, demonstrated that APJ and ORL1 heterodimerize in HEK293 cells. We found that the APJ-ORL1 heterodimer is selectively activated by apelin-13, which causes the dimer to couple to Gαi proteins and reduce the recruitment of GRKs and β-arrestins to the dimer. We showed that the APJ-ORL1 dimer exhibits biased signaling, in which G protein-dependent signaling pathways override β-arrestin-dependent signaling pathways. Our results demonstrate that the structural interface of the APJ-ORL1 dimer switches from transmembrane domain TM1/TM2 in the inactive state to TM5 in the active state. We used mutational analysis and BRET assays to identify key residues in TM5 (APJ L218, APJ I224, and ORL1 L229) responsible for the receptor-receptor interaction. These results provide important information on the APJ-ORL1 heterodimer and may assist the design of new drugs targeting biased signaling pathways for treatment of pain and cardiovascular and metabolic diseases.
Topics: Humans; Apelin; GTP-Binding Proteins; HEK293 Cells; Neuroblastoma; Receptors, G-Protein-Coupled; Receptors, Opioid; Signal Transduction
PubMed: 37364634
DOI: 10.1016/j.lfs.2023.121892 -
Biochemistry. Biokhimiia Nov 2023Creation of bioactive molecules for treatment of cardiovascular diseases based on natural peptides is the focus of intensive experimental research. In the recent years,... (Review)
Review
Creation of bioactive molecules for treatment of cardiovascular diseases based on natural peptides is the focus of intensive experimental research. In the recent years, it has been established that C-terminal fragments of apelin, an endogenous ligand of the APJ receptor, reduce metabolic and functional disorders in experimental heart damage. The review presents literature data and generalized results of our own experiments on the effect of apelin-13, [Pyr]apelin-13, apelin-12, and their chemically modified analogues on the heart under normal and pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of action of apelin peptides on the damaged myocardium includes decrease in the death of cardiomyocytes from necrosis, reduction of damage to cardiomyocyte membranes, improvement in myocardial metabolic state, and decrease in formation of reactive oxygen species and lipid peroxidation products. The mechanisms of protective action of these peptides associated with activation of the APJ receptor and manifestation of antioxidant properties are discussed. The data presented in the review show promise of the molecular design of APJ receptor peptide agonists, which can serve as the basis for the development of cardioprotectors that affect the processes of free radical oxidation and metabolic adaptation.
Topics: Humans; Apelin; Apelin Receptors; Myocardium; Myocytes, Cardiac; Cardiovascular Diseases; Receptors, G-Protein-Coupled
PubMed: 38105205
DOI: 10.1134/S0006297923110160 -
Scientific Reports Oct 2023During atherosclerotic plaque formation, smooth muscle cells (SMCs) switch from a contractile/differentiated to a synthetic/dedifferentiated phenotype. We previously...
During atherosclerotic plaque formation, smooth muscle cells (SMCs) switch from a contractile/differentiated to a synthetic/dedifferentiated phenotype. We previously isolated differentiated spindle-shaped (S) and dedifferentiated rhomboid (R) SMCs from porcine coronary artery. R-SMCs express S100A4, a calcium-binding protein. We investigated the role of apelin in this phenotypic conversion, as well as its relationship with S100A4. We found that apelin was highly expressed in R-SMCs compared with S-SMCs. We observed a nuclear expression of apelin in SMCs within experimentally-induced intimal thickening of the porcine coronary artery and rat aorta. Plasmids targeting apelin to the nucleus (N. Ap) and to the secretory vesicles (S. Ap) were transfected into S-SMCs where apelin was barely detectable. Both plasmids induced the SMC transition towards a R-phenotype. Overexpression of N. Ap, and to a lesser degree S. Ap, led to a nuclear localization of S100A4. Stimulation of S-SMCs with platelet-derived growth factor-BB, known to induce the transition toward the R-phenotype, yielded the direct interaction and nuclear expression of both apelin and S100A4. In conclusion, apelin induces a SMC phenotypic transition towards the synthetic phenotype. These results suggest that apelin acts via nuclear re-localization of S100A4, raising the possibility of a new pro-atherogenic relationship between apelin and S100A4.
Topics: Animals; Rats; Apelin; Atherosclerosis; Cell Movement; Cells, Cultured; Myocytes, Smooth Muscle; Phenotype; Swine
PubMed: 37907514
DOI: 10.1038/s41598-023-45470-z -
Apelin, APJ, and ELABELA: Role in Placental Function, Pregnancy, and Foetal Development-An Overview.Cells Dec 2021The apelinergic system, which includes the apelin receptor (APJ) as well as its two specific ligands, namely apelin and ELABELA (ELA/APELA/Toddler), have been the... (Review)
Review
The apelinergic system, which includes the apelin receptor (APJ) as well as its two specific ligands, namely apelin and ELABELA (ELA/APELA/Toddler), have been the subject of many recent studies due to their pleiotropic effects in humans and other animals. Expression of these factors has been investigated in numerous tissues and organs-for example, the lungs, heart, uterus, and ovary. Moreover, a number of studies have been devoted to understanding the role of apelin and the entire apelinergic system in the most important processes in the body, starting from early stages of human life with regulation of placental function and the proper course of pregnancy. Disturbances in the balance of placental processes such as proliferation, apoptosis, angiogenesis, or hormone secretion may lead to specific pregnancy pathologies; therefore, there is a great need to search for substances that would help in their early diagnosis or treatment. A number of studies have indicated that compounds of the apelinergic system could serve this purpose. Hence, in this review, we summarized the most important reports about the role of apelin and the entire apelinergic system in the regulation of placental physiology and pregnancy.
Topics: Amino Acid Sequence; Animals; Apelin; Apelin Receptors; Female; Fetus; Humans; Models, Biological; Peptide Hormones; Placenta; Pregnancy
PubMed: 35011661
DOI: 10.3390/cells11010099 -
International Journal of Biological... 2023Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of...
Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of the G-protein-coupled receptor (APJ), is abundantly expressed in diverse organs. The apelin-APJ axis helps to control pathological and physiological processes in lung. The role of apelin in the pathological process and its possible therapeutic effects on silicosis have not been elucidated. In this study, we found that lung expression and circulating levels of apelin were markedly decreased in silicosis patients and silica-induced fibrotic mice and associated with the severity. Furthermore, data demonstrated that pre-treatment from day 3 and post-treatment from day 15 with apelin could both alleviate silica-induced pulmonary fibrosis in mice. Besides, apelin inhibited pulmonary fibroblast activation via transforming growth factor beta 1 (TGF-β1) signaling. Our study suggested that apelin could prevent and reverse silica-induced pulmonary fibrosis by inhibiting the fibroblast activation through TGF-β1 signaling pathway, thus providing a new potential therapeutic strategy for silicosis and other pulmonary fibrosis.
Topics: Animals; Mice; Apelin; Fibroblasts; Pulmonary Fibrosis; Silicon Dioxide; Silicosis; Transforming Growth Factor beta1
PubMed: 37705751
DOI: 10.7150/ijbs.81436 -
Journal of Cellular Biochemistry Apr 2023The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as...
The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.
Topics: Animals; Apelin; Zebrafish; Spironolactone; Platelet Aggregation; Peptide Hormones; Signal Transduction; Apelin Receptors; Thrombosis; Cerebral Infarction
PubMed: 36855998
DOI: 10.1002/jcb.30392 -
Renal Failure Dec 2023Contrast-induced acute kidney injury (CI-AKI) is a severe complication associated with significant morbidity and mortality, and effective therapeutic strategies are...
Contrast-induced acute kidney injury (CI-AKI) is a severe complication associated with significant morbidity and mortality, and effective therapeutic strategies are still lacking. Apelin is an endogenous physiological regulator with antioxidative, anti-inflammatory and antiapoptotic properties. However, the role of apelin-13 in CI-AKI remains unclear. In our study, we found that the protein expression levels of apelin were significantly downregulated in rat kidney tissues and HK-2 cells during contrast media treatment. Moreover, we explored the protective effect of apelin-13 on renal tubule damage using and models of CI-AKI. Exogenous apelin-13 ameliorated endoplasmic reticulum stress, reactive oxygen species and apoptosis protein expression in contrast media-treated cells and rat kidney tissues. Mechanistically, the downregulation of endoplasmic reticulum stress contributed critically to the antiapoptotic effect of apelin-13. Collectively, our findings reveal the inherent mechanisms by which apelin-13 regulates CI-AKI and provide a prospective target for the prevention of CI-AKI.
Topics: Animals; Rats; Apelin; Contrast Media; Endoplasmic Reticulum Stress; Acute Kidney Injury
PubMed: 37723076
DOI: 10.1080/0886022X.2023.2179852 -
Frontiers in Oncology 2021Apelin is an endogenous ligand that binds to the G protein-coupled receptor angiotensin-like-receptor 1 (APJ). Apelin and APJ are widely distributed in organs and... (Review)
Review
Apelin is an endogenous ligand that binds to the G protein-coupled receptor angiotensin-like-receptor 1 (APJ). Apelin and APJ are widely distributed in organs and tissues and are involved in multiple physiological and pathological processes including cardiovascular regulation, neuroendocrine stress response, energy metabolism, etc. Additionally, apelin/APJ axis was found to play an important role in cancer development and progression. Apela is a newly identified endogenous ligand for APJ. Several studies have revealed the potential role of Apela in cancers. In this article, we review the current studies focusing on the role of apelin/APJ signaling and Apela in different cancers. Potential mechanisms by which apelin/APJ and Apela mediate the regulation of cancer development and progression were also mentioned. The Apelin/APJ signaling and Apela may serve as potential therapeutic candidates for treatment of cancer.
PubMed: 33912466
DOI: 10.3389/fonc.2021.658253 -
Theriogenology Apr 2020Apelin is a potent inotropic agent causing endothelium-mediated vasodilation and is involved in vessel formation by interacting with a specific receptor. Its...
Apelin is a potent inotropic agent causing endothelium-mediated vasodilation and is involved in vessel formation by interacting with a specific receptor. Its cardiovascular profile suggests a role in the regulation of gestational hemodynamic changes. The expression of apelin and its receptor has been reported in some portions of the reproductive tract of different mammalian species. As far as we know, there are no reports describing the expression of apelin and apelin receptor in bitch's placenta. Therefore, the aim of this study was to investigate, for the first time, the presence and distribution of apelin and apelin receptor in bitch placenta by molecular biology and immunohistochemical techniques. Sixteen adult female half-breed bitches were used. The animals were divided into two groups based on the stage of pregnancy: group 1 (mid-gestation n = 8) and group 2 (end gestation n = 8). These bitches were subjected to ovariohysterectomy (group1) or non-conservative caesarean section (group 2). The immunohistochemical technique revealed the presence of positive immune reaction for apelin and apelin receptor in all the samples examined at 30 days and at the end of pregnancy. In particular, apelin and apelin receptor staining was evident in the cytoplasms of cytotrophoblasts and in epithelial cells of the maternal portion. Even if not included into the structure of the placenta, the uterine glands also exhibited a positive immune reaction for apelin and apelin receptor. The RT-PCR analysis showed the presence of transcripts for apelin and apelin receptor in all the placenta samples examined. On the basis of our results it was also possible to hypothesize a potential role of apelin in the control of local placenta blood flow during pregnancy development in bitches.
Topics: Animals; Apelin; Apelin Receptors; Dogs; Female; Gene Expression Regulation; Placenta; Pregnancy
PubMed: 31767185
DOI: 10.1016/j.theriogenology.2019.11.016