-
Advances in Medical Sciences Mar 2020Apelin is an endogenous peptide, which is expressed in a vast board of organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose... (Review)
Review
Apelin is an endogenous peptide, which is expressed in a vast board of organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose tissues. The apelin receptor, called angiotensin-like-receptor 1 (APJ), is also expressed in the brain, spleen, placenta, heart, liver, intestine, prostate, thymus, testis, ovary, lungs, kidneys, stomach, and adipose tissue. The apelin/APJ axis is involved in a number of physiological and pathological processes. The apelin expression is increased in various kinds of cancer and the apelin/APJ axis plays a key role in the development of tumors through enhancing angiogenesis, metastasis, cell proliferation and also through the development of cancer stem cells and drug resistance. The apelin also stops the apoptosis of cancer cells. The apelin/APJ axis was considered in this review as an attractive therapeutic target for cancer treatment.
Topics: Animals; Apelin; Apelin Receptors; Disease Progression; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 32087570
DOI: 10.1016/j.advms.2020.02.002 -
Archives of Toxicology Sep 2023The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients'...
The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients' quality of life. This study was designed to investigate the effect of apelin-13 on cisplatin-induced C57BL/6 mice hearing loss model and explore the potential underlying molecular mechanisms. Mice were intraperitoneally injected with 100 μg/kg apelin-13 2 h before 3 mg/kg cisplatin injection for 7 consecutive days. Cochlear explants cultured in vitro were pretreated with 10 nM apelin-13 2 h prior to 30 μM cisplatin treatment for another 24 h. Hearing test and morphology results showed that apelin-13 attenuated cisplatin-induced mice hearing loss and protected cochlear hair cells and spiral ganglion neurons from damage. In vivo and in vitro experimental results showed that apelin-3 reduced cisplatin-induced apoptosis of hair cells and spiral ganglion neurons. In addition, apelin-3 preserved mitochondrial membrane potential and inhibited ROS production in cultured cochlear explants. Mechanistic studies showed that apelin-3 decreased cisplatin-induced cleaved caspase 3 expression but increased Bcl-2; inhibited the expression of pro-inflammatory factors TNF-a and IL-6; and increased STAT1 phosphorylation but decreased STAT3 phosphorylation. In conclusion, our results indicate that apelin-13 could be a potential otoprotective agent to prevent cisplatin-induced ototoxicity by inhibiting apoptosis, ROS production, TNF-α and IL-6 expression, and regulating phosphorylation of STAT1 and STAT3 transcription factors.
Topics: Mice; Animals; Cisplatin; Antineoplastic Agents; Apelin; Ototoxicity; Reactive Oxygen Species; Interleukin-6; Quality of Life; Mice, Inbred C57BL; Hearing Loss; Apoptosis
PubMed: 37395757
DOI: 10.1007/s00204-023-03544-x -
Current Molecular Pharmacology 2021Among the various orphan G protein-coupled receptors, apelin receptor (APJ), originally identified in the human genome as an orphan G-protein-coupled receptor, was... (Review)
Review
Among the various orphan G protein-coupled receptors, apelin receptor (APJ), originally identified in the human genome as an orphan G-protein-coupled receptor, was deorphanised in 1998 with the discovery of its endogenous ligand, apelin. Apelin and APJ mRNA are widely expressed in peripheral tissues and the central nervous system in mammals. In this review, we discuss the characteristics, pharmacology, physiology, and pathology of the apelin/APJ system in mammals. Several physiological roles of the apelin/APJ system have been reported, including in homeostasis, cardiovascular maintenance, angiogenesis, and neuroprotection. In cellular signaling, apelin has been shown to drive the PI3K/Akt, MAPK, and PKA signaling pathways, leading to cell proliferation and protection from excitotoxicity. Apelin is also found in breast milk; therefore, apelin is believed to contribute to the establishment of the infant immune system. Furthermore, activation of the apelin/APJ system is reported to restore muscular weakness associated with aging. Thus, the apelin/APJ system represents a novel target for the prevention of several important cardiovascular and neurodegenerative diseases and the maintenance of health during old age.
Topics: Angiogenesis Inducing Agents; Animals; Apelin; Apelin Receptors; Biomarkers; Heart; Homeostasis; Humans; Immune System; Mitogen-Activated Protein Kinase Kinases; Muscle Weakness; Neuroprotection; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 32484774
DOI: 10.2174/1874467213666200602133032 -
FASEB Journal : Official Publication of... Jun 2020Like apelin (pE13F, K17F), Elabela/Toddler is an endogenous ligand of the apelin receptor playing a key role in cardiovascular development. Elabela/Toddler exists as...
Like apelin (pE13F, K17F), Elabela/Toddler is an endogenous ligand of the apelin receptor playing a key role in cardiovascular development. Elabela/Toddler exists as peptide fragments of 32 (Q32P), 22 (K22P) and 11 (C11P) amino acids. In this study, we investigated the possible structural and functional similarities between these endogenous ligands. We performed in vitro pharmacological characterization and biased signaling analyses for apelin and Elabela/Toddler fragments in CHO cells, by assessing binding affinities, the inhibition of cyclic adenosine monophosphate (cAMP) production and the triggering of ß-arrestin 2 recruitment. We also performed Alanine scanning for Elabela/Toddler and structure-function studies based on site-directed mutagenesis of the rat and human apelin receptor, to compare the modes of binding of the different endogenous ligands. Alanine scanning of K22P showed that neither of its cysteine residues were involved in binding or in peptide activity and that its C-terminus carried the key pharmacophore for receptor binding and activation. We showed that Asp and Asp of rat and human apelin receptor, respectively, were not involved in Elabela/Toddler activity, whereas they are key residues for apelin binding and activity. We found that the structural features of Elabela/Toddler and apelin were different, resulting in different modes of binding of these endogenous ligands to the apelin receptor. These differences should be taken into account in the future development metabolically stable analogs of Elabela/Toddler and apelin as potential therapeutic tools for the treatment of cardiovascular diseases and water retention/hyponatremic disorders.
Topics: Animals; Apelin Receptors; CHO Cells; Cardiovascular Diseases; Cell Line; Cricetulus; Cyclic AMP; Cysteine; Humans; Hyponatremia; Peptide Fragments; Peptide Hormones; Rats; Signal Transduction
PubMed: 32301550
DOI: 10.1096/fj.201903029R -
Chinese Medical Journal May 2022Hypertension is the leading risk factor for global mortality and morbidity and those with hypertension are more likely to develop severe symptoms in cardiovascular and... (Review)
Review
Hypertension is the leading risk factor for global mortality and morbidity and those with hypertension are more likely to develop severe symptoms in cardiovascular and cerebrovascular system, which is closely related to abnormal renin-angiotensin system and elabela/apelin-apelin receptor (APJ) axis. The elabela/apelin-APJ axis exerts essential roles in regulating blood pressure levels, vascular tone, and cardiovascular dysfunction in hypertension by counterbalancing the action of the angiotensin II/angiotensin II type 1 receptor axis and enhancing the endothelial nitric oxide (NO) synthase/NO signaling. Furthermore, the elabela/apelin-APJ axis demonstrates beneficial effects in cardiovascular physiology and pathophysiology, including angiogenesis, cellular proliferation, fibrosis, apoptosis, oxidative stress, and cardiovascular remodeling and dysfunction during hypertension. More importantly, effects of the elabela/apelin-APJ axis on vascular tone may depend upon blood vessel type or various pathological conditions. Intriguingly, the broad distribution of elabela/apelin and alternative isoforms implicates its distinct functions in diverse cardiac and vascular cells and tissue types. Finally, both loss-of-function and gain-of-function approaches have defined critical roles of the elabela/apelin-APJ axis in reducing the development and severity of hypertensive diseases. Thus, targeting the elabela/apelin-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of hypertension, and an increased understanding of cardiovascular actions of the elabela/apelin-APJ axis will help to develop effective interventions for hypertension. In this review, we focus on the physiology and biochemistry, diverse actions, and underlying mechanisms of the elabela/apelin-APJ axis, highlighting its role in hypertension and hypertensive cardiovascular injury and dysfunction, with a view to provide a prospective strategy for hypertensive disease therapy.
Topics: Apelin; Apelin Receptors; Humans; Hypertension; Peptide Hormones; Prospective Studies
PubMed: 34608073
DOI: 10.1097/CM9.0000000000001766 -
Respiratory Physiology & Neurobiology Sep 2023Interstitial lung diseases (ILD) are a heterogenic group of respiratory diseases with complex pathogenesis. A growing number of evidence suggests role of adipose tissue...
Interstitial lung diseases (ILD) are a heterogenic group of respiratory diseases with complex pathogenesis. A growing number of evidence suggests role of adipose tissue and it's hormones (adipokines) in pathogenesis of various disorders, including lung tissue diseases. The aim of this study was to assess the concentrations of selected adipokines and their receptors (apelin, adiponectin, chemerin, chemerin receptor - CMKLR1) in patients with IPF (idiopathic pulmonary fibrosis) and sarcoidosis in comparison to healthy controls. We found changes in adipokines concentrations in ILD. Adiponectin concentrations were higher in all respiratory diseases patients in comparison to healthy controls. Apelin concentration in ILD patients was higher then those in healthy subjects. The trend of chemerin and CMKLR1 concentrations were similar, with highest concentrations seen in sarcoidosis. The study shows a difference of adipokines concentrations between patients with ILD and healthy controls. Adipokines are a potential marker and therapeutic target in patients with IPF and sarcoidosis.
Topics: Humans; Adipokines; Apelin; Adiponectin; Lung Diseases, Interstitial; Idiopathic Pulmonary Fibrosis; Sarcoidosis; Respiratory Tract Diseases
PubMed: 37393966
DOI: 10.1016/j.resp.2023.104109 -
International Journal of Molecular... Mar 2023Apelin is an endogenous ligand for the G protein-coupled receptor APJ and has multiple biological activities in human tissues and organs, including the heart, blood... (Review)
Review
Apelin is an endogenous ligand for the G protein-coupled receptor APJ and has multiple biological activities in human tissues and organs, including the heart, blood vessels, adipose tissue, central nervous system, lungs, kidneys, and liver. This article reviews the crucial role of apelin in regulating oxidative stress-related processes by promoting prooxidant or antioxidant mechanisms. Following the binding of APJ to different active apelin isoforms and the interaction with several G proteins according to cell types, the apelin/APJ system is able to modulate different intracellular signaling pathways and biological functions, such as vascular tone, platelet aggregation and leukocytes adhesion, myocardial activity, ischemia/reperfusion injury, insulin resistance, inflammation, and cell proliferation and invasion. As a consequence of these multifaceted properties, the role of the apelinergic axis in the pathogenesis of degenerative and proliferative conditions (e.g., Alzheimer's and Parkinson's diseases, osteoporosis, and cancer) is currently investigated. In this view, the dual effect of the apelin/APJ system in the regulation of oxidative stress needs to be more extensively clarified, in order to identify new potential strategies and tools able to selectively modulate this axis according to the tissue-specific profile.
Topics: Humans; Apelin; Apelin Receptors; Oxidative Stress; Receptors, G-Protein-Coupled
PubMed: 36902176
DOI: 10.3390/ijms24054745 -
Cellular and Molecular Life Sciences :... Aug 2020Apelin is an endogenous ligand of G protein-coupled receptor APJ. It is extensively expressed in many tissues such as heart, liver, and kidney, especially in lung... (Review)
Review
Apelin is an endogenous ligand of G protein-coupled receptor APJ. It is extensively expressed in many tissues such as heart, liver, and kidney, especially in lung tissue. A growing body of evidence suggests that apelin/APJ system is closely related to the development of respiratory diseases. Therefore, in this review, we focus on the role of apelin/APJ system in respiratory diseases, including pulmonary arterial hypertension (PAH), pulmonary embolism (PE), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), obstructive sleep apnoea syndrome (OSAS), non-small cell lung cancer (NSCLC), pulmonary edema, asthma, and chronic obstructive pulmonary diseases. In detail, apelin/APJ system attenuates PAH by activating AMPK-KLF2-eNOS-NO signaling and miR424/503-FGF axis. Also, apelin protects against ALI/ARDS by reducing mitochondrial ROS-triggered oxidative damage, mitochondria apoptosis, and inflammatory responses induced by the activation of NF-κB and NLRP3 inflammasome. Apelin/APJ system also prevents the occurrence of pulmonary edema via activating AKT-NOS3-NO pathway. Moreover, apelin/APJ system accelerates NSCLC cells' proliferation and migration via triggering ERK1/2-cyclin D1 and PAK1-cofilin signaling, respectively. Additionally, apelin/APJ system may act as a predictor in the development of OSAS and PE. Considering the pleiotropic actions of apelin/APJ system, targeting apelin/APJ system may be a potent therapeutic avenue for respiratory diseases.
Topics: Apelin; Apelin Receptors; Humans; Lung Diseases; Lung Neoplasms; MicroRNAs; NF-kappa B; Oxidoreductases; Protein Kinases; Signal Transduction
PubMed: 32128601
DOI: 10.1007/s00018-020-03461-7 -
Cells Oct 2019Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms.... (Review)
Review
Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology-both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB and CB receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.
Topics: Apelin; Carrier Proteins; Endocannabinoids; Enterohepatic Circulation; Fibrosis; Humans; Hypertension, Portal; Inflammation; Liver; Liver Circulation; Liver Cirrhosis; Portal System
PubMed: 31653030
DOI: 10.3390/cells8111311 -
Biological Research For Nursing Oct 2023Preeclampsia (PE) is a multifunctional and multisystem disorder. Several factors favor the development of PE, including obesity. Cytokines are also expressed in the...
BACKGROUND
Preeclampsia (PE) is a multifunctional and multisystem disorder. Several factors favor the development of PE, including obesity. Cytokines are also expressed in the placenta, predisposing to local alterations that favor the development of distinct pathological processes, including PE. This study aimed to evaluate the apelin and visfatin mRNA expression in the placental tissue of women with preeclampsia and overweight/obesity and correlates with maternal and fetal variables.
METHODS
A cross-sectional analytical study was performed with 60 pregnant women and their newborns. Clinical, anthropometric, and laboratory variables were collected. Placental tissue samples were obtained, and the apelin and visfatin mRNA expression levels were assessed by qRT-PCR.
RESULTS
The main findings evidenced lower levels of apelin expression in overweight/obese women, accompanied by a negative correlation with BMI and pre-pregnancy weight; a higher expression of apelin was also observed in women with late PE and no personal history of PE. For visfatin levels, higher expression levels were observed in women with late PE and term delivery. Furthermore, a positive correlation was observed between visfatin levels and fetal anthropometric parameters, such as weight, length, and head circumference.
CONCLUSION
Apelin levels were less expressed in overweight/obese women. Apelin and visfatin levels were correlated/associated with maternal-fetal variables.
Topics: Female; Pregnancy; Humans; Infant, Newborn; Apelin; Pre-Eclampsia; Placenta; Overweight; Nicotinamide Phosphoribosyltransferase; Cross-Sectional Studies; Cytokines; Obesity; RNA, Messenger
PubMed: 37246238
DOI: 10.1177/10998004231178835