Elabela is a newly discovered peptide in recent years.It is the endogenous ligand of Apelin receptor(APJ)and plays an important role in embryonic development and adult organs.Elabela-APJ axis is closely related to organ fibrosis.Elabela can protect the functions of heart and kidney by antagonizing renin-angiotensin system and regulating blood pressure.In addition,it can prevent kidney and heart fibrosis by down-regulating the expression of fibrosis and inflammatory factors.However,there is a positive correlation between the level of Elabela and the degree of liver fibrosis,suggesting that Elabela may play a role in promoting liver fibrosis.This review aims to explore the role of Elabela-APJ axis in renal fibrosis,cardiac fibrosis,and liver fibrosis,and to provide a new therapeutic target for organ fibrosis.
Apelin ; Apelin Receptors ; Blood Pressure ; Female ; Fibrosis ; Humans ; Peptide Hormones ; Pregnancy

OBJECTIVETo study the effects of swimming exercise on the expression of apelin and its receptor (APJ) system in pulmonary tissues of rats with pulmonary hypertension induced by hypoxia.

METHODSForty-five male SD rats were randomly divided into control group, hypoxia group (seven-week) and swimming group (four-week swimming group after three-week hypoxia). The animal model of hypoxic pulmonary hypertension was established by exposing the rats to isobaric hypoxic chamber (8 h/d, 6 d/w). The rats of swimming group swam 60 min/day, 7 d/week for 4 weeks after three-week hypoxia. The mean pulmonary arterial pressure (mPAP) and the mean carotid arterial pressure (mCAP) were measured by either right or left cardiac catheterization, and the weight ratio of right ventricule/left ventricle plus septum [RV/(LV + S)] were calculated. The Masson's trichrome stained lung specimens were used by light microscope to examine the vessel wall area/total area (WA/TA), vessel cavity area/total area (CA/TA) and media thickness of pulmonary arterioles (PAMT). Meanwhile, apelin/ APJ expressions were determined by Western blot and immunohistochemistry.

RESULTS(1) mPAP and RV/(LV + S) of hypoxia group were higher than those of control group by 73.6% and 31.2% (P < 0.01), and mPAP and RV/(LV + S) of swimming group were lower than those of hypoxia group by 21.1%and 8.9 % (P < 0.05), respectively. (2) Masson's trichrome staining revealed that WA/TA and PAMT of hypoxia group were higher than those of control group by 70.8% and 102%. However, WA/TA and PAMT of swimming group were lower than those of hypoxia group by 24.8% and 40.1% (all P < 0.01), respectively. CA/TA of hypoxia group was lower than that of control group by 15.1%, and CA/TA of swimming group was lower than that of hypoxia group by 10.3% (all P < 0.01). (3) Compared with control group, hypoxia group showed up-regulated apelin expression and down-regulated APJ expression in pulmonary tissues (all P < 0.01). Compared with hypoxia group, swimming group showed decreased apelin expression and elevated APJ expression in pulmonary tissues (all P < 0.01). (4) Apelin localized mainly in intracytoplasm of inflammatory cell and tunica adventitia of vessel, and APJ were in vascular intima and tunica externa and plasmalemma of inflammatory cell.

CONCLUSIONThe improving effect of swimming exercise on hypoxic pulmonary hypertension in rats could be mediated by regulating the pulmonary apelin/APJ system.

Animals ; Apelin ; Apelin Receptors ; Hypertension, Pulmonary ; metabolism ; Hypoxia ; metabolism ; Intercellular Signaling Peptides and Proteins ; metabolism ; Male ; Physical Conditioning, Animal ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; metabolism ; Swimming

OBJECTIVETo explore the role of bromodomain and extra terminal (BET) bromodomain in hematopoietic differentiation from human enbryonic stem cells (hESC).

METHODSThe effect of BET hematopoietic inhibitor I-BET151 on hematopoietic differentiation from hESC was detected by using a monolayer hematopoietic defferentiation model, immunofluorescence, flow cytometry and real-time PCR; moreover the role of I-BET151 in process of hematopoietic differentiation was explored by adding I-BET151 in different differentiation stages.

RESULTSThe analysis results of immunofluorescence, flow cytometry and real-time PCR showed that I-BET 151 significantly inhibited the generation of CD43 positive hematopoietic stem and progenitor cells (HSPCs). It was found that the addition of I-BET 151 in different stages, including APLNR lateral plate mesoderm production, CD34CD31 hemogenic endothelium (HEP) generation and endothelial-to-hematopoietic transition, significantly suppressed the generation of CD43 positive hematopoietic progenitor cells.

CONCLUSIONI-BET 151 inhibites hematopoietic differentiation from hESCs at several stages, suggesting that the BET bromodomain plays important roles in multiple stages of hematopoietic differentiation from hESCs.

Apelin Receptors ; Cell Differentiation ; Flow Cytometry ; Hemangioblasts ; Hematopoietic Stem Cells ; Human Embryonic Stem Cells ; Humans

OBJECTIVETo observe the change of apelin and its receptor (APJ) in the lung tissue of rats with pulmonary hypertension induced by monocrotaline and to explore its significance.

METHODSTwenty-five male SD rats were randomly divided into control group (n = 10) and monocrotaline group (n = 15). On the twenty-first day after the rats were intraperitoneally injected 60 mg/kg monocrotaline for monocrotaline group or equal volume vehicle for control group, the mean pulmonary artery pressure was measured by right heart catheterization. Histopathological study of lung tissue was done with hematoxylin-eosin (HE) and Masson's trichrome staining. The concentration of apelin in the plasma was measured by radioimmunoassay. The expressions of apelin/APJ proteins and genes in lung tissue were measured respectively by Western blot and reverse transcription polymerase chain reaction (RT-PCR).

RESULTSThe mean pulmonary arterial pressure, right ventricular hypertrophy, pulmonary vascular remodeling index, content of apelin protein in lung tissue of monocrotaline group were higher than those in control group. APJ protein and gene expression in monocrotaline group were significantly lower than those in control group (P < 0.01, P < 0.05), but apelin gene expression in the lung tissue between the two groups had no significant difference.

CONCLUSIONEndogenous apelin/APJ dysfunction may play an important role in the development of pulmonary hypertension induced by monocrotaline.

Animals ; Apelin ; Apelin Receptors ; Hypertension, Pulmonary ; chemically induced ; metabolism ; Intercellular Signaling Peptides and Proteins ; metabolism ; Lung ; metabolism ; Male ; Monocrotaline ; adverse effects ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; metabolism

OBJECTIVETo investigate peripheral blood apelin levels in patients with acute ST-elevation myocardial infarction (STEMI) and their correlation with the one-year outcome of the patients.

METHODSA total of 153 consecutive patients, including 93 with acute STEMI undergoing primary percutaneous coronary intervention (PCI), 30 with acute STEMI and 30 with stable angina all undergoing elective PCI, and 10 healthy control subjects were examined for peripheral blood apelin levels and clinical parameters. The composite endpoints (CEPs) were determined at the one year follow-up.

RESULTSApelin levels were significantly decreased in all the patients at admission, but increased following primary PCI. Apelin levels showed a negative correlation with glycosylated hemoglobin levels. At one year following PCI, the patients with a lower apelin level showed an increased risk for lowered left ventricular ejection fraction ratio, but further analysis failed to provide evidence that apelin levels were predictive of the one-year outcome.

CONCLUSIONPeripheral blood apelin levels might be useful for predicting the clinical outcomes of patients with acute STEMI.

Acute Disease ; Apelin ; Biomarkers ; blood ; Case-Control Studies ; Humans ; Intercellular Signaling Peptides and Proteins ; blood ; Myocardial Infarction ; blood ; diagnosis ; Percutaneous Coronary Intervention ; Prognosis ; Ventricular Function, Left

OBJECTIVETo preliminarily investigate the relationship between serum apelin level and pulmonary artery pressure in children with congenital heart disease.

METHODSOne hundred and twenty-six children with congenital heart disease undergoing surgical treatment were enrolled as subjects. The serum level of apelin was determined before surgery and at 7 days after surgery. The ratio of pulmonary artery systolic pressure to aortic systolic pressure (Pp/Ps) was calculated before extracorporeal circulation. According to the Pp/Ps value, patients were classified into non-pulmonary arterial hypertension (PAH) group, mild PAH group, moderate PAH group, and severe PAH group. Pulmonary artery mean pressure was estimated by echocardiography at 7 days after surgery.

RESULTSThe non-PAH group had the highest serum level of apelin before and after surgery, followed by the mild PAH group, moderate PAH group, and severe PAH group (P<0.05). All groups had significantly increased serum levels of apelin at 7 days after surgery (P<0.05). The serum level of apelin was negatively correlated with pulmonary artery pressure before surgery (r=-0.51, P<0.05) and at 7 days after surgery (r=-0.54, P<0.05).

CONCLUSIONSThe decrease in serum apelin level is associated with the development of pulmonary hypertension in children with congenital heart disease. The significance of serum apelin in predicting the development and degree of pulmonary hypertension in children with congenital heart disease deserves further studies.

Apelin ; Blood Pressure ; Child, Preschool ; Female ; Heart Defects, Congenital ; blood ; physiopathology ; Humans ; Hypertension, Pulmonary ; blood ; Infant ; Intercellular Signaling Peptides and Proteins ; blood ; Male ; Pulmonary Artery ; physiopathology

OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE^-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE^-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE^-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE^-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.
Mice ; Animals ; Apelin ; Tissue Plasminogen Activator/metabolism* ; Quercetin/therapeutic use* ; AMP-Activated Protein Kinases/metabolism* ; Sirtuin 1/metabolism* ; Signal Transduction/physiology* ; Atherosclerosis/metabolism* ; Apolipoproteins E

OBJECTIVETo investigate whether ginsenoside-Rb1 (Gs-Rb1) inhibits the apoptosis of hypoxia cardiomyocytes by up-regulating apelin-APJ system and whether the system is affected by hypoxia-induced factor 1α (Hif-1α).

METHODSNeonatal rat cardiomyocytes were randomly divided into 6 groups: a control group, a simple CoCl group, a simple Gs-Rb1 group, a CoCl and Gs-Rb1 hypoxia group, a CoCl and 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) group, a CoCl and YC-1 group and a Gs-Rb1 group, in which YC-1 inhibits the synthesis and accelerates the degradation of Hif-1a. The concentration of CoCl, Gs-Rb1 and YC-1 was 500 μmol/L, 200 μmol/L and 5 μmol/L, respectively; the apoptosis ratio was analyzed with a flow cytometer; and apelin, APJ and Hif-1α were assayed with immunocytochemistry, Western blot assays and reverse transcription polymerase chain reaction (RT-PCR).

RESULTS(1) The anti-apoptosis effect of Gs-Rb1 on hypoxia cardiomyocytes was significantly inhibited by YC-1; (2) Hypoxia significantly up-graded the expression of mRNA and protein of apelin; this effect was further reinforced by Gs-Rb1 and significantly inhibited by YC-1; (3) Gs-Rb1 further strengthened the expression of APJ mRNA and APJ proteins once hypoxia occurred, which was significantly inhibited by YC-1; (4) Gs-Rb1 significantly increased the expression of Hif-1α, which was completely abolished by YC-1; (5) There was a negative relationship between AR and apelin (or APJ, including mRNA and protein), a positive correlation between apelin (or APJ) protein and Hif-1a protein, in hypoxia cardiomyocytes.

CONCLUSIONThe apelin-APJ system plays an important role in the anti-apoptosis effect of Gs-Rb1 on hypoxia neonatal cardiomyocytes, which was partly adjusted by Hif-1α.

Animals ; Animals, Newborn ; Apelin ; Apelin Receptors ; Cell Hypoxia ; drug effects ; Ginsenosides ; pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins ; genetics ; metabolism ; Myocytes, Cardiac ; cytology ; drug effects ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Rats, Wistar ; Receptors, G-Protein-Coupled ; metabolism

BACKGROUNDApoptosis is a major cause of ischemic heart dysfunction. Apelin, the endogenous ligand for the G-protein-coupled APJ receptor, has been reported to exert cardioprotective effects during myocardial injury. The aim of this study was to investigate the effects of apelin on apoptosis of rat cardiomyocytes induced by glucose deprivation (GD) and study the related signaling pathway.

METHODSApelin and APJ mRNA expression were determined by RT-PCR in neonatal rat cardiomyocytes during different durations of GD. Cardiomyocyte apoptosis was detected by annexin V-FITC/propidium iodide (PI) staining after GD for 12 hours with or without apelin-13 (10 and 100 nmol/L) pretreatment. Protein levels of Akt and the mammalian target of rapamycin (mTOR) as well as cell apoptosis were detected in the presence or absence of LY294002 (a phosphatidylinositol 3-kinases (PI3K) inhibitor) or rapamycin (a mTOR inhibitor).

RESULTSApelin mRNA expression was up-regulated when cardiomyocytes were exposed to GD for 6, 12, 18, and 24 hours compared with the base level (P > 0.05, P < 0.01, P < 0.01, P < 0.01). However, when cardiomyocytes were exposed to GD for up to 36 hours, apelin mRNA expression was 17% lower than the base level (P < 0.05). APJ mRNA expression paralleled that of apelin. Apelin-13 pretreatment at 100 nmol/L significantly inhibited GD-induced cardiomyocyte apoptosis (P < 0.05) and increased Akt and mTOR phosphorylation (P < 0.01, P < 0.01). At the same time apelin-13 (100 nmol/L) up-regulated Bcl-2 protein expression and down-regulated Bax and cleaved caspase-3 expression (P < 0.01, P < 0.05, P < 0.05). The anti-apoptotic effect of apelin-13 was blocked by LY294002 (P < 0.01) but not by rapamycin.

CONCLUSIONSThe endogenous apelin-APJ system is compensatorily up-regulated and ultimately down-regulated following sustained myocardial ischemia. Apelin protects against ischemic cardiomyocyte apoptosis via activation of the PI3K/Akt pathway.

Animals ; Apelin ; Apelin Receptors ; Apoptosis ; Carrier Proteins ; genetics ; physiology ; Caspase 3 ; analysis ; Cell Survival ; Cells, Cultured ; Glucose ; deficiency ; Intercellular Signaling Peptides and Proteins ; Myocytes, Cardiac ; physiology ; Phosphatidylinositol 3-Kinases ; physiology ; Proto-Oncogene Proteins c-akt ; physiology ; Proto-Oncogene Proteins c-bcl-2 ; analysis ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; physiology ; Signal Transduction ; bcl-2-Associated X Protein ; analysis

OBJECTIVETo explore the effect of puerarin combined with felodipine on the mRNA and protein expression of apelin and APJ in renal tissue of renovascular hypertensive rat.

METHODSixty-two Sprague-Dawley rats were used, of which 8 rats were randomly chosen as sham-operation group. The remaining rats were made for the rat model with renovascular hypertension. The renovascular hypertensive rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (0.8 mg x kg(-1) x d(-1)), puerarin (50 mg x kg(-1) x d(-1)), puerarin combined with felodipine (puerarin 25 mg x kg(-1) x d(-1) + felodipine 0.4 mg x kg(-1) x d(-1)) or captopril combined with felodipine (captopril 15 mg x kg(-1) x d(-1) x felodipine 0.4 mg x kg(-1) x d(-1)), and 1 group which was treated with distilled water. Drugs or distilled water were administered for 8 weeks. The expression of apelin and APJ mRNA and protein in ischemic and non-ischemic kidneys was assessed by RT-PCR or Western blot.

RESULTCompared with sham-operation group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys in model group was increased significantly (P < 0.01); the expression of APJ mRNA and protein in ischemic kidneys had no significance, while that in non-ischemic kidneys was decreased (P < 0. 01). Compared with model group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys was decreased significantly in all drug-treated groups (P < 0.01); while that of APJ mRNA and protein in non-ischemic kidneys was upregulated (P < 0.01). Compared with felodipine group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys was decreased (P < 0.01 or P < 0.05) in the group treated with both puerarin and felodipine; and the expression of APJ mRNA and protein in ischemic kidneys did not reach significant level, however, that was upregulated in non-ischemic kidneys (P < 0.01 or P < 0.05).

CONCLUSIONPuerarin downregulates the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys, and upregulates that of APJ mRNA and protein in non-ischemic kidneys. Combination of puerarin and felodipine enhances the above-mentioned effects and shows no significant difference versus the combination of felodipine and captopril. The results suggest that puerarin regulates blood pressure and protects target organ through apelin/APJ pathway and that puerarin has synergetic effects with CCB.

Animals ; Antihypertensive Agents ; pharmacology ; Apelin ; Apelin Receptors ; Blotting, Western ; Captopril ; pharmacology ; Drug Synergism ; Felodipine ; pharmacology ; Gene Expression ; drug effects ; Hypertension, Renovascular ; genetics ; metabolism ; Intercellular Signaling Peptides and Proteins ; genetics ; metabolism ; Ischemia ; Isoflavones ; pharmacology ; Kidney ; blood supply ; drug effects ; metabolism ; Male ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Vasodilator Agents ; pharmacology