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Frontiers in Endocrinology 2022Nowadays, diabetes and obesity are two main health-threatening metabolic disorders in the world, which increase the risk for many chronic diseases. Apelin, a peptide... (Review)
Review
Nowadays, diabetes and obesity are two main health-threatening metabolic disorders in the world, which increase the risk for many chronic diseases. Apelin, a peptide hormone, exerts its effect by binding with angiotensin II protein J receptor (APJ) and is considered to be linked with diabetes and obesity. Apelin and its receptor are widely present in the body and are involved in many physiological processes, such as glucose and lipid metabolism, homeostasis, endocrine response to stress, and angiogenesis. In this review, we summarize the literatures on the role of the Apelin-APJ system in diabetes and obesity for a better understanding of the mechanism and function of apelin and its receptor in the pathophysiology of diseases that may contribute to the development of new therapies.
Topics: Apelin; Apelin Receptors; Diabetes Mellitus, Type 2; Humans; Intercellular Signaling Peptides and Proteins; Obesity
PubMed: 35355561
DOI: 10.3389/fendo.2022.820002 -
Comprehensive Physiology Dec 2017Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions... (Review)
Review
Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions have been implicated in regulation of the adipoinsular axis, cardiovascular system, and central nervous system alongside pathological processes. Each ligand may be processed into a variety of bioactive isoforms endogenously, with apelin ranging from 13 to 55 amino acids and apela from 11 to 32, typically being cleaved C-terminal to dibasic proprotein convertase cleavage sites. The C-terminal region of the respective precursor protein is retained and is responsible for receptor binding and subsequent activation. Interestingly, both apelin and apela exhibit isoform-dependent variability in potency and efficacy under various physiological and pathological conditions, but most studies focus on a single isoform. Biophysical behavior and structural properties of apelin and apela isoforms show strong correlations with functional studies, with key motifs now well determined for apelin. Unlike its ligands, the AR has been relatively difficult to characterize by biophysical techniques, with most characterization to date being focused on effects of mutagenesis. This situation may improve following a recently reported AR crystal structure, but there are still barriers to overcome in terms of comprehensive biophysical study. In this review, we summarize the three components of the apelinergic system in terms of structure-function correlation, with a particular focus on isoform-dependent properties, underlining the potential for regulation of the system through multiple endogenous ligands and isoforms, isoform-dependent pharmacological properties, and biological membrane-mediated receptor interaction. © 2018 American Physiological Society. Compr Physiol 8:407-450, 2018.
Topics: Amino Acid Sequence; Apelin; Crystallization; Humans; Molecular Structure; Peptide Hormones; Structure-Activity Relationship
PubMed: 29357134
DOI: 10.1002/cphy.c170028 -
Journal of Translational Medicine Nov 2023Long noncoding RNAs (lncRNAs) play a key role in the occurrence and progression of myopia. However, the function of lncRNAs in retinal ganglion cells (RGCs) in the...
BACKGROUND
Long noncoding RNAs (lncRNAs) play a key role in the occurrence and progression of myopia. However, the function of lncRNAs in retinal ganglion cells (RGCs) in the pathogenesis of myopia is still unknown. The aim of our study was to explore the lncRNA-mediated competing endogenous RNA (ceRNA) network in RGCs during the development of myopia.
METHODS
RNA sequencing was performed to analyze lncRNA and mRNA expression profiles in RGCs between guinea pigs with form-deprived myopia (FDM) and normal control guinea pigs, and related ceRNA networks were constructed. Then, potentially important genes in ceRNA networks were verified by qRT‒PCR, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore biological functions in the RGCs of FDM guinea pigs. The important genes and related signaling pathways were further verified by qRT‒PCR, immunohistochemistry, immunofluorescence and Western blot in myopia in FDM guinea pigs, FDM mice, and highly myopic adults.
RESULTS
The distribution of RGCs was uneven, the number of RGCs was decreased, and RGC apoptosis was increased in FDM guinea pigs. In total, 873 lncRNAs and 2480 mRNAs were determined to be differentially expressed genes in RGCs from normal control and FDM guinea pigs. Via lncRNA-mediated ceRNA network construction and PCR verification, we found that lncRNA-XR_002792574.1 may be involved in the development of myopia through the miR-760-3p/Adcy1 pathway in RGCs. Further verification in FDM guinea pigs, FDM mice, and highly myopic adults demonstrated that the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis in RGCs might be related to cGMP/PKG, the apelin signaling pathway and scleral remodeling.
CONCLUSION
We demonstrated that the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis in RGCs might be related to myopia. On the one hand, the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis might inhibit the cGMP/PKG and apelin signaling pathways in RGCs, thereby causing RGC damage in myopia. On the other hand, the lncRNA-XR_002792574.1/miR-760-3p/Adcy1 axis may cause myopic scleral remodeling through the ERK-MMP-2 pathway. These findings may reveal novel potential targets in myopia and provide reference value for exploration and development of gene editing therapeutics for hereditary myopia.
Topics: Mice; Animals; Guinea Pigs; MicroRNAs; RNA, Long Noncoding; Apelin; Retinal Ganglion Cells; Gene Regulatory Networks; Biomarkers; Myopia
PubMed: 37932794
DOI: 10.1186/s12967-023-04662-x -
Pharmacology & Therapeutics Oct 2018Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions... (Review)
Review
Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions of the brain. A growing body of evidence now demonstrates a regulatory role for the apelin/APJ receptor system in cardiovascular physiology and pathophysiology, thus making it a potential target for cardiovascular drug discovery and development. Indeed, ongoing studies are investigating the potential benefits of apelin and apelin-mimetics for disorders such as heart failure and pulmonary arterial hypertension. Apelin causes relaxation of isolated arteries, and systemic administration of apelin typically results in a reduction in systolic and diastolic blood pressure and an increase in blood flow. Nonetheless, vasopressor responses and contraction of vascular smooth muscle in response to apelin have also been observed under certain conditions. The goal of the current review is to summarize major findings regarding the apelin/APJ receptor system in blood vessels, with an emphasis on regulation of vascular tone, and to identify areas of investigation that may provide guidance for the development of novel therapeutic agents that target this system.
Topics: Animals; Apelin; Apelin Receptors; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Heart Failure; Humans; Hypertension, Pulmonary; Ligands; Muscle, Smooth, Vascular
PubMed: 29807055
DOI: 10.1016/j.pharmthera.2018.05.013 -
Frontiers in Endocrinology 2022The prevalence of maternal obesity during pregnancy is associated with the risk of gestational diabetes, preeclampsia, and cardiomyopathy. Environmental factors such as... (Review)
Review
The prevalence of maternal obesity during pregnancy is associated with the risk of gestational diabetes, preeclampsia, and cardiomyopathy. Environmental factors such as active lifestyles and apelin may lead to beneficial changes. In rats, apelin and exercise (45 to 65% VO for 6 to 9 weeks) during pregnancy increase brown adipose tissue (BAT) proteins such as Cidea, Elovl3, UCP1, PRDM16, and PGC-1α in males and females fetuses, while white adipose tissue (WAT) is reduced. In humans and animals, apelin and exercise stimulate the expression of the glucose transporters (GLUT1/2/4) in the muscle and adipose tissue through the PI3K/Akt and AMPK pathways. Hence, exercise and apelin may are known as regulators of energy metabolism and be anti-obesity and anti-diabetic properties. In mice, exercise also creates a short-term hypoxic environment in the pregnant mother, activating HIF-1, VEGF, and VEGFR, and increasing angiogenesis. Exercise and apelin also increase vasodilation, angiogenesis, and suppression of inflammation through the L-arginine/eNOS/NO pathway in humans. Exercise can stimulate the ACE2-Ang-(1-7)-Mas axis in parallel with inhibiting the ACE-Ang II-AT1 pathway. Exercise and apelin seem to prevent preeclampsia through these processes. In rats, moderate-intensity exercise (60 to 70% VO for 8 weeks) and apelin/APJ also may prevent pathological hypertrophy in pregnancy by activating the PI3K/Akt/mTOR/p70S6K pathway, PI3k-Akt-ERK1/2-p70S6K pathway, and the anti-inflammatory cytokine IL-10. Since pre-clinical studies have been more on animal models, future research with scientific guidelines should pay more attention to human specimens. In future research, time factors such as the first, second, and third trimesters of pregnancy and the intensity and duration of exercise are important variables that should be considered to determine the optimal intensity and duration of exercise.
Topics: Adipose Tissue, Brown; Animals; Apelin; Female; Humans; Male; Mice; Phosphatidylinositol 3-Kinases; Pre-Eclampsia; Pregnancy; Proto-Oncogene Proteins c-akt; Rats; Ribosomal Protein S6 Kinases, 70-kDa
PubMed: 36093083
DOI: 10.3389/fendo.2022.965167 -
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 -
Acta Biochimica Et Biophysica Sinica Jul 2013Apelin is a bioactive peptide discovered recently that has been proved to be an endogenous ligand of the APJ receptor. Apelin and APJ are widely distributed in the... (Review)
Review
Apelin is a bioactive peptide discovered recently that has been proved to be an endogenous ligand of the APJ receptor. Apelin and APJ are widely distributed in the central nervous system and peripheral tissues. Researches have confirmed that apelin/APJ involved in a wide range of physiological and pathological functions in the cardiovascular system. Investigations indicated that apelin is a novel critical factor in the development of atherosclerosis (AS). In this review, we discuss the roles of apelin in the vascular smooth muscle cell proliferation, monocytes-endothelial cell adhesion, and angiogenesis that potentially reveals a new cellular mechanism of AS. Considering these roles, apelin and APJ may be novel therapeutic targets of AS.
Topics: Animals; Apelin; Apelin Receptors; Atherosclerosis; Cell Adhesion; Cell Adhesion Molecules; Chemokines; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Lipid Metabolism; Muscle, Smooth, Vascular; Receptors, G-Protein-Coupled
PubMed: 23588025
DOI: 10.1093/abbs/gmt040 -
Nature Reviews. Nephrology Dec 2021Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment... (Review)
Review
Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment for CKD is blockade of the renin-angiotensin-aldosterone system (RAAS), which reduces blood pressure and proteinuria and slows kidney function decline. Despite this treatment, many patients progress to kidney failure, which requires dialysis or kidney transplantation, and/or die as a result of cardiovascular disease. The apelin system is an endogenous physiological regulator that is emerging as a potential therapeutic target for many diseases. This system comprises the apelin receptor and its two families of endogenous ligands, apelin and elabela/toddler. Preclinical and clinical studies show that apelin receptor ligands are endothelium-dependent vasodilators and potent inotropes, and the apelin system has a reciprocal relationship with the RAAS. In preclinical studies, apelin regulates glomerular haemodynamics and acts on the tubule to promote aquaresis. In addition, apelin is protective in several kidney injury models. Although the apelin system has not yet been studied in patients with CKD, the available data suggest that apelin is a promising potential therapeutic target for kidney disease.
Topics: Apelin; Apelin Receptors; Cardiovascular Diseases; Humans; Ligands; Renal Insufficiency, Chronic; Renin-Angiotensin System
PubMed: 34389827
DOI: 10.1038/s41581-021-00461-z