-
Heart Failure Reviews Jul 2015Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterized by different numbers of amino acids. The number of amino acids... (Review)
Review
Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterized by different numbers of amino acids. The number of amino acids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes in apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long-lasting (6 h) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling.
Topics: Animals; Apelin; Cardiovascular System; Heart Failure; Humans; Intercellular Signaling Peptides and Proteins
PubMed: 25652330
DOI: 10.1007/s10741-015-9475-x -
ELife Apr 2023We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell...
We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, , and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.
Topics: Acute Lung Injury; Animals; Mice; Regenerative Medicine; Apelin; Endothelial Cells; Mice, Transgenic; Lung
PubMed: 37078698
DOI: 10.7554/eLife.80900 -
Cytokine Sep 2023Apelin/APJ receptor (R) is involved in many oxidative stress-induced pathological conditions. Since this system is not yet explored in male reproduction, we studied...
Apelin/APJ receptor (R) is involved in many oxidative stress-induced pathological conditions. Since this system is not yet explored in male reproduction, we studied apelin/APJ-R in human semen and testis. Semen of 41 infertile patients with varicocele, genitourinary infections, unexplained infertility and 12 fertile men was analysed (WHO guidelines, 2021). Apelin was quantified by ELISA in seminal fluid and spermatozoa, interleukin (IL)-1β in seminal fluid. Apelin/APJ-R were immunolocalized in spermatozoa and testis. Apelin was present in spermatozoa and its levels were negatively correlated with normal sperm morphology% (r = -0.857; p < 0.001), and positively with IL-1β levels (r = 0.455; p < 0.001). Apelin and IL-1β concentrations were increased in patients' samples with varicocele (apelin p < 0.01; IL-1β p < 0.05) and infections (apelin p < 0.01; IL-1β p < 0.001). By logistic regression analysis, apelin (OR 1.310; p = 0.011) and IL-1β (OR 1.572; p = 0.005) were predictors of inflammatory diseases (varicocele, infections). Apelin and APJ-R immunofluorescence labels were weak in sperm tail of fertile men and intense along tail, cytoplasmic residues and post-acrosomal sheath of sperm from infertile men. In testis, apelin and APJ-R labels were evident in Leydig cells and weak inside the seminiferous tubule. Apelin/APJ-R system is present in human spermatozoa and testicular tissue and probably involved in human fertility.
Topics: Humans; Male; Apelin; Infertility, Male; Semen; Spermatozoa; Testis; Varicocele
PubMed: 37352775
DOI: 10.1016/j.cyto.2023.156281 -
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 -
PloS One 2022The present systematic review and meta-analysis aimed to ascertain if the circulating levels of apelin, as an important regulator of the cardiovascular homeostasis,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The present systematic review and meta-analysis aimed to ascertain if the circulating levels of apelin, as an important regulator of the cardiovascular homeostasis, differ in patients with cardiovascular diseases (CVDs) and controls.
METHODS
A comprehensive search was performed in electronic databases including PubMed, Scopus, EMBASE, and Web of Science to identify the studies addressing apelin in CVD up to April 5, 2021. Due to the presence of different units to measure the circulating levels of apelin across the included studies, they expressed the standardized mean difference (SMD) and their 95% confidence interval (CI) as summary effect size. A random-effects model comprising DerSimonian and Laird method was used to pool SMDs.
RESULTS
Twenty-four articles (30 studies) comprised of 1793 cases and 1416 controls were included. Pooled results obtained through random-effects model indicated that apelin concentrations in the cases' blood samples were significantly lower than those of the control groups (SMD = -0.72, 95% CI: -1.25, -0.18, P = 0.009; I2 = 97.3%, P<0.001). New combined biomarkers showed a significant decrease in SMD of apelin/high-density lipoprotein cholesterol (apelin/HDL-C) ratio [-5.17; 95% CI, -8.72, -1.63, P = 0.000; I2 = 99.0%], apelin/low-density lipoprotein cholesterol (apelin/LDL-C) ratio [-4.31; 95% CI, -6.08, -2.55, P = 0.000; I2 = 98.0%] and apelin/total cholesterol (apelin/TC) ratio [-17.30; 95% CI, -22.85, -11.76, P = 0.000; I2 = 99.1%]. However, no significant differences were found in the SMD of apelin/triacylglycerol (apelin/TG) ratio in cases with CVDs compared to the control group [-2.96; 95% CI, -7.41, 1.49, P = 0.000; I2 = 99.2%].
CONCLUSION
The association of apelin with CVDs is different based on the region and disease subtypes. These findings account for the possible usefulness of apelin as an additional biomarker in the diagnosis of CVD in diabetic patients and in the diagnosis of patients with CAD. Moreover, apelin/HDL-c, apelin/LDL-c, and apelin/TC ratios could be offered as diagnostic markers for CVD.
Topics: Apelin; Biomarkers; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Humans; Triglycerides
PubMed: 35913970
DOI: 10.1371/journal.pone.0271899 -
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 -
International Journal of Molecular... May 2023Apelin, as a cardiokine/myokine, is emerging as an important regulator of cardiac and skeletal muscle homeostasis. Loss of apelin signaling results in premature cardiac...
Apelin, as a cardiokine/myokine, is emerging as an important regulator of cardiac and skeletal muscle homeostasis. Loss of apelin signaling results in premature cardiac aging and sarcopenia. However, the contribution of apelin to peak athletic performance remains largely elusive. In this paper, we assessed the impact of maximal cardiorespiratory exercise testing on the plasma apelin levels of 58 male professional soccer players. Circulating apelin-13 and apelin-36, on average, increased transiently after a single bout of treadmill exercise; however, apelin responses (Δapelin = peak - baseline values) showed a striking interindividual variability. Baseline apelin-13 levels were inversely correlated with those of Δapelin-13 and Δapelin-36. Δapelin-13 showed a positive correlation with the maximal metabolic equivalent, relative maximal O consumption, and peak circulatory power, whereas such an association in the case of Δapelin-36 could not be detected. In conclusion, we observed a pronounced individual-to-individual variation in exercise-induced changes in the plasma levels of apelin-13 and apelin-36. Since changes in plasma apelin-13 levels correlated with the indicators of physical performance, whole-body oxygen consumption and pumping capability of the heart, apelin, as a novel exerkine, may be a determinant of peak athletic performance.
Topics: Male; Humans; Apelin; Exercise; Muscle, Skeletal; Sarcopenia; Athletic Performance; Oxygen Consumption
PubMed: 37175901
DOI: 10.3390/ijms24098195 -
Frontiers in Endocrinology 2022Apelin (APLN), as a ligand for APJ (an orphan G-protein-coupled receptor), is an adipokine with pleiotropic effects in many physiological processes of the body. It has...
Apelin (APLN), as a ligand for APJ (an orphan G-protein-coupled receptor), is an adipokine with pleiotropic effects in many physiological processes of the body. It has an important role in the control of reproduction particularly in females (mainly in control of ovarian function). This study was carried out to investigate the mRNA and protein amounts of APLN/APJ in granulose cells (GCs) of ovarian follicles with small (SF), medium (MF), and large (LF) sizes of buffalo () and the effect of IGF1 and follicle-stimulating hormone (FSH) on the expression levels of APLN/APJ. In addition, we evaluated the effect of various doses of APLN (isoforms -13 and -17) singly or in combination with IGF1 and FSH on estradiol (E2) and progesterone (P4) secretion in GCs. The mRNA and protein abundance of APLN was the highest in GCs of LF while the APJ expression enhanced with follicle enlargement in GCs (p-value <0.01). IGF1 and FSH elevated the mRNA and protein amounts of APLN and FSH, and IGF1 increased the expression of APJ in buffalo GCs (p-value <0.01). Both isoforms of APLN (-13/-17) singly or in the presence of IGF1 or FSH increased the secretion of E2 and P4 with or without preincubation of cells with APJ antagonist (ML221 10 µM), although we had some variation in the effects. Concurrently, APLN-13/-17 significantly increased the mRNA and protein expression of CYP19A1 and StAR (p-value <0.01). ML221 substantially diminished the secretion of E2 and P4 and also the expression of CY19A1 and StAR in buffalo GCs (p-value <0.01). We also revealed that APLN-13/-17 (10 M), singly or in response to IGF1 and FSH, increased the production of E2 and P4 in different times of stimulation. In conclusion, APLN may play a crucial role in steroidogenesis and follicular development in ovarian GCs of buffalo.
Topics: Animals; Apelin; Apelin Receptors; Buffaloes; Female; Granulosa Cells; Ovary
PubMed: 35355567
DOI: 10.3389/fendo.2022.844360 -
Veterinary Research Communications Jun 2023Apelin, a member of the adipokine family, is a novel endogenous peptide which regulates the male reproductive system of mammals by interacting with a specific receptor....
Apelin, a member of the adipokine family, is a novel endogenous peptide which regulates the male reproductive system of mammals by interacting with a specific receptor. Recent studies have highlighted that apelin may play a role in the regulation of reproduction by reducing testosterone production and inhibiting LH secretion. To the best of our knowledge, there is no available data on the presence of the apelin and its receptor in canine testes. Therefore, the aim of this study was to reveal the presence of apelin and evaluate its distribution in the canine testes using immunohistochemical and RT-PCR techniques. For this purpose, five fertile and healthy male dogs were subjected to elective orchiectomy. The immunohistochemical reaction revealed the presence of apelin and its receptor in the canine testes. Apelin was localized in spermatids and spermatozoa with a positive signal in the "acrosomal bodies". As regards the apelin receptor, a positive immunoreaction was detected in the cytoplasm of the cells localized near to the basal membrane of the seminiferous tubules and in the cytoplasm of Leydig cells. The RT-PCR analysis showed the presence of transcripts for apelin and apelin receptor in all of the samples under study. A 35kDa band confirmed apelin receptor protein expression in all of the samples analysed. In conclusion, the paracrine and endocrine role of apelin and its cognate receptor on male reproduction reported in humans and laboratory animals could also be hypothesized in dogs.
Topics: Humans; Dogs; Animals; Male; Testis; Apelin; Apelin Receptors; Reverse Transcriptase Polymerase Chain Reaction; Spermatozoa; Canidae
PubMed: 36331787
DOI: 10.1007/s11259-022-10001-0 -
Stroke Jun 2023Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous shunts, bypassing the...
BACKGROUND
Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous shunts, bypassing the artery-capillary-vein network and disrupting blood flow. Clinically, bAVM treatments are invasive and not routinely applicable. There is critical need to understand mechanisms of bAVM pathologies and develop pharmacological therapies.
METHODS
We used an in vivo mouse model of Rbpj-mediated bAVM, which develops pathologies in the early postnatal period and an siRNA in vitro system to knockdown RBPJ in human brain microvascular endothelial cells (ECs). To understand molecular events regulated by endothelial Rbpj, we conducted RNA-Seq and chromatin immunoprecipitation-Seq analyses from isolated brain ECs.
RESULTS
Rbpj-deficient (mutant) brain ECs acquired abnormally rounded shape (with no change to cell area), altered basement membrane dynamics, and increased endothelial cell density along arteriovenous shunts, compared to controls, suggesting impaired remodeling of neonatal brain vasculature. Consistent with impaired endothelial cell dynamics, we found increased Cdc42 (cell division cycle 42) activity in isolated mutant ECs, suggesting that Rbpj regulates small GTPase (guanosine triphosphate hydrolase)-mediated cellular functions in brain ECs. siRNA-treated, -deficient human brain ECs displayed increased Cdc42 activity, disrupted cell polarity and focal adhesion properties, and impaired migration in vitro. RNA-Seq analysis from isolated brain ECs identified differentially expressed genes in mutants, including , which encodes a ligand for G protein-coupled receptor signaling known to influence small GTPase activity. Chromatin immunoprecipitation-Seq analysis revealed chromatin loci occupied by Rbpj in brain ECs that corresponded to G-protein and Apelin signaling molecules. In vivo administration of a competitive peptide antagonist against the Apelin receptor (Aplnr/Apj) attenuated Cdc42 activity and restored endothelial cell morphology and arteriovenous connection diameter in Rbpj-mutant brain vessels.
CONCLUSIONS
Our data suggest that endothelial Rbpj promotes rearrangement of brain ECs during cerebrovascular remodeling, through Apelin/Apj-mediated small GTPase activity, and prevents bAVM. By inhibiting Apelin/Apj signaling in vivo, we demonstrated pharmacological prevention of Rbpj-mediated bAVM.
Topics: Animals; Humans; Infant, Newborn; Mice; Apelin; Arteriovenous Malformations; Brain; Cell Cycle; Endothelial Cells; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Monomeric GTP-Binding Proteins; Receptors, G-Protein-Coupled; RNA, Small Interfering; Vascular Remodeling
PubMed: 37051908
DOI: 10.1161/STROKEAHA.122.041853