Sacubitril/valsartan attenuates left ventricular remodeling and improve cardiac function by upregulating apelin/APJ pathway in rats with heart failure / 中华心血管病杂志

Objective: To investigate the effect and mechanism of sacubitril/valsartan on left ventricular remodeling and cardiac function in rats with heart failure. Methods: A total of 46 SPF-grade male Wistar rats weighed 300-350 g were acclimatized to the laboratory for 7 days. Rats were then divided into 4 groups: the heart failure group (n=12, intraperitoneal injection of adriamycin hydrochloride 2.5 mg/kg once a week for 6 consecutive weeks, establishing a model of heart failure); heart failure+sacubitril/valsartan group (treatment group, n=12, intragastric administration with sacubitril/valsartan 1 week before the first injection of adriamycin, at a dose of 60 mg·kg-1·d-1 for 7 weeks); heart failure+sacubitril/valsartan+APJ antagonist F13A group (F13A group, n=12, adriamycin and sacubitril/valsartan, intraperitoneal injection of 100 μg·kg-1·d-1 APJ antagonist F13A for 7 weeks) and control group (n=10, intraperitoneal injection of equal volume of normal saline). One week after the last injection of adriamycin or saline, transthoracic echocardiography was performed to detect the cardiac structure and function, and then the rats were executed, blood and left ventricular specimens were obtained for further analysis. Hematoxylin-eosin staining and Masson trichrome staining were performed to analyze the left ventricular pathological change and myocardial fibrosis. TUNEL staining was performed to detect cardiomyocyte apoptosis. mRNA expression of left ventricular myocardial apelin and APJ was detected by RT-qRCR. ELISA was performed to detect plasma apelin-12 concentration. The protein expression of left ventricular myocardial apelin and APJ was detected by Western blot. Results: Seven rats survived in the heart failure group, 10 in the treatment group, and 8 in the F13A group. Echocardiography showed that the left ventricular end-diastolic diameter (LVEDD) and the left ventricular end-systolic diameter (LVESD) were higher (both P<0.05), while the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were lower in the heart failure group than in the control group (both P<0.05). Compared with the heart failure group, rats in the treatment group were featured with lower LVEDD and LVESD (both P<0.05), higher LVEF and LVFS (both P<0.05), these beneficial effects were reversed in rats assigned to F13A group (all P<0.05 vs. treatment group). The results of HE staining showed that the cardiomyocytes of rats in the control group were arranged neatly and densely structured, the cardiomyocytes in the heart failure group were arranged in disorder, distorted and the gap between cells was increased, the cardiomyocytes in the treatment group were slightly neat and dense, and cardiomyocytes in the F13A group were featured similarly as the heart failure group. Masson staining showed that there were small amount of collagen fibers in the left ventricular myocardial interstitium of the control group, while left ventricular myocardial fibrosis was significantly increased, and collagen volume fraction (CVF) was significantly higher in the heart failure group than that of the control group (P<0.05). Compared with the heart failure group, the left ventricular myocardial fibrosis and the CVF were reduced in the treatment group (both P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). TUNEL staining showed that the apoptosis index (AI) of cardiomyocytes in rats was higher in the heart failure group compared with the control group (P<0.05), which was reduced in the treatment group (P<0.05 vs. heart failure group), this effect again was reversed in the F13A group (P<0.05 vs. treatment group). The results of RT-qPCR and Western blot showed that the mRNA and protein levels of apelin and APJ in left ventricular myocardial tissue of rats were downregulated in heart failure group (all P<0.05) compared with the control group. Compared with the heart failure group, the mRNA and protein levels of apelin and APJ were upregulated in the treatment group (all P<0.05), these effects were reversed in the F13A group (all P<0.05 vs. treatment group). ELISA test showed that the plasma apelin concentration of rats was lower in the heart failure group compared with the control group (P<0.05); compared with the heart failure group, the plasma apelin concentration of rats was higher in the treatment group (P<0.05), this effect was reversed in the F13A group (P<0.05 vs. treatment group). Conclusion: Sacubitril/valsartan can partially reverse left ventricular remodeling and improve cardiac function in rats with heart failure through modulating Apelin/APJ pathways.

The Impact of Transcatheter Aortic Valve Implantation (TAVI) on Serum Apelin Levels in Patients with Aortic Valvular Stenosis

Abstract Introduction: In this study, we aimed to investigate the impact of transcatheter aortic valve implantation (TAVI) on serum apelin levels in patients with severe symptomatic aortic valve stenosis (AS). Methods: Forty-six consecutive patients (76.9±7.4 years, n=27 women) who underwent TAVI and 45 age- and sex-matched control subjects were included in the study. Echocardiographic parameters, serum apelin, pro-brain natriuretic peptide (Pro-BNP), and troponin I levels were compared between the groups. In addition, the preprocedural and first-month follow-up echocardiographic parameters and serum apelin values of TAVI patients were compared. Results: Serum median troponin I and Pro-BNP levels were significantly higher and serum apelin levels were significantly lower in TAVI patients before TAVI procedure than in the control subjects (P<0.001, for all). Median troponin I and Pro-BNP levels were significantly decreased and apelin levels were significantly increased after TAVI procedure compared to the peri-procedural levels. There was a significant and moderate negative correlation between Pro-BNP and apelin levels measured before and after TAVI procedure. A statistically significant and strong negative correlation was found between aortic valve area and Pro-BNP level before TAVI procedure, while a statistically significant but weak positive correlation was found between valve area and apelin level. Conclusion: In our study, apelin levels were significantly lower and Pro-BNP levels were higher in AS patients compared with the control group. Moreover, after TAVI procedure, a significant increase in apelin levels and a significant decrease in Pro-BNP levels were observed. There was also a negative and moderate correlation between apelin and Pro-BNP levels.

Research Progress on Role and Mechanism of Elabela in Organ Fibrosis / 中国医学科学院学报

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.

Serum irisin and apelin levels and markers of atherosclerosis in patients with subclinical hypothyroidism

ABSTRACT Objective: In this study, we aimed to evaluate serum irisin and apelin levels in patients with subclinical hypothyroidism (SCH) when they were subclinical hypothyroid and become euthyroid after levothyroxine therapy and association of these adipokines with markers of atherosclerosis such as serum homocysteine levels and carotid intima-media thickness (IMT). Subjects and methods: The study included 160 patients with newly diagnosed subclinical hypothyroidism due to Hashimoto's thyroiditis and 86 euthyroid healty subjects. Serum glucose and lipid profile, insulin, HOMA, TSH, free T3, free T4, anti-thyroperoxidase and anti-thyroglobulin antibodies, homocysteine, apelin and irisin levels were measured in all study subjects. Thyroid and carotid ultrasound examinations were performed. The subclinical hypothyroid group was reevaluated after 12-weeks of levothyroxine therapy when they became euthyroid. Results: Clinical characteristics of the patient and control group were similar. Glucose, insulin and HOMA levels, lipid parameters and free T3 were similar between the two groups.. Serum homocystein was higher and apelin was lower in patients with SCH, but irisin levels were similar between the two groups. While thyroid volume was lower, carotid IMT was significantly greater in patients with SCH (pCarotidIMT:0,01). After 12-weeks of levothyroxine therapy, all the studied parameters remained unchanged except, serum freeT4, TSH, homocystein and apelin. While homocystein decreased (p: 0,001), apelin increased significantly (p = 0,049). In multivariate analysis, low apelin levels significantly contributed to carotid IMT (p = 0,041). Conclusions: Apelin-APJ system may play a role in vascular and cardiac dysfunction in patients with SCH and treatment of this condition may improve the risk of cardiovascular disease.

A preliminary investigation of relationship between serum apelin level and pulmonary artery pressure in children with congenital heart disease / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To preliminarily investigate the relationship between serum apelin level and pulmonary artery pressure in children with congenital heart disease.</p><p><b>METHODS</b>One 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.</p><p><b>RESULTS</b>The 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).</p><p><b>CONCLUSIONS</b>The 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.</p>

Apelin-APJ effects of ginsenoside-Rb1 depending on hypoxia-induced factor 1α in hypoxia neonatal cardiomyocytes / 中国结合医学杂志

<p><b>OBJECTIVE</b>To 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).</p><p><b>METHODS</b>Neonatal 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).</p><p><b>RESULTS</b>(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.</p><p><b>CONCLUSION</b>The 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.</p>

Peripheral blood apelin level in patients with acute ST-elevation myocardial infarction and its prognostic value / 南方医科大学学报

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>A 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.</p><p><b>RESULTS</b>Apelin 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.</p><p><b>CONCLUSION</b>Peripheral blood apelin levels might be useful for predicting the clinical outcomes of patients with acute STEMI.</p>

Changes of apelin and its receptor in lung tissue of rats with pulmonary hypertension induced by monocrotaline / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>Twenty-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).</p><p><b>RESULTS</b>The 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.</p><p><b>CONCLUSION</b>Endogenous apelin/APJ dysfunction may play an important role in the development of pulmonary hypertension induced by monocrotaline.</p>

Effect of puerarin combined with felodipine on mRNA and protein expression of apelin and APJ in renovascular hypertensive rat / 中国中药杂志

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHOD</b>Sixty-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.</p><p><b>RESULT</b>Compared 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).</p><p><b>CONCLUSION</b>Puerarin 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.</p>

Chemerin and apelin are positively correlated with inflammation in obese type 2 diabetic patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>As two novel adipocytokines, chemerin and apelin play a key role in the pathological process of insulin resistance (IR), glucose metabolism and obesity, researchers have found that the levels of chemerin and apelin changed significantly in type 2 diabetic patients with obesity, however, the underlying mechanism involved remains unclear. The aim of this study was to investigate whether chemerin and apelin play an important role in the pathophysiologic proceeding of diabetes.</p><p><b>METHODS</b>This study enrolled 81 newly diagnosed obese type 2 diabetes mellitus (T2DM) patients (T2DM group, n = 81). All the patients were randomly assigned to DM1 group treated with metformin (n = 41) and DM2 group treated with pioglitazone (n = 40). After hypoglycemic agents treatment, patients under better blood glucose control were chosen to be given antioxidant treatment. Another 79 subjects without T2DM were recruited as normal control group (NC group), including 40 subjects (NC1 group) with normal body mass index (BMI) and 39 obese subjects (NC2 group). Levels of chemerin, apelin, BMI, tumor necrosis factor-α (TNF-α), homeostasis model assessment of IR (HOMA-IR) and 8-isoprotaglandim F2α (8-iso-PGF2α) were examined at baseline and post-treatment. The relationship between chemerin, apelin and BMI, TNF-α, HOMA-IR, 8-iso-PGF2α was analyzed.</p><p><b>RESULTS</b>The baseline levels of chemerin, apelin, TNF-α, HOMA-IR and 8-iso-PGF2α in T2DM group were significantly higher than normal control group (P < 0.001). All indices mentioned above were significantly decreased after treatment (P < 0.05). In T2DM patients treated with pioglitazone, indices mentioned above except for HOMA-IR, were decreased significantly compared with patients treated with metformin (P < 0.05). After antioxidant treatment using lipoic acid, levels of chemerin, apelin, TNF-α and 8-iso-PGF2α were further significantly decreased (P < 0.05). Correlation analysis showed that the levels of chemerin and apelin correlated positively with BMI, TNF-α, HOMA-IR and 8-iso-PGF2α before and after treatment with hypoglycemic agents (P < 0.01). The levels of chemerin and apelin also had positive correlation with TNF-α and 8-iso-PGF2α after antioxidant treatment (P < 0.05).</p><p><b>CONCLUSIONS</b>The levels of chemerin and apelin in obese T2DM patients are closely related to IR. The increased levels may be a result of compensatory response to IR, and also may be the causative factor of IR. The levels of chemerin and apelin correlate closely with oxidative stress and inflammation. The two adipokines may be inflammatory factors playing important roles in the initiation and development of obese T2DM. Chemerin and apelin are related to the pathophysiology of IR, oxidative stress and inflammation.</p>

Effect of swimming exercise on the expression of apelin and its receptor in pulmonary tissues of rats with hypoxic pulmonary hypertension / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>Forty-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.</p><p><b>RESULTS</b>(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.</p><p><b>CONCLUSION</b>The improving effect of swimming exercise on hypoxic pulmonary hypertension in rats could be mediated by regulating the pulmonary apelin/APJ system.</p>

Effect of apelin on vasodilatation of isolated pulmonary arteries in rats is concerned with the nitric oxide pathway / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the effect of apelin on vasodilatation of isolated pulmonary arterial rings in rats and its relationship to the nitric oxide (NO) pathway, and to observe the difference of vasodilatation between hypoxic rats and normoxic rats.</p><p><b>METHODS</b>Thirty-six male Sprague-Dawley (SD) rats were randomly divided into hypoxic group and normoxic group. The effects of accumulated apelin on pulmonary arterial rings preconstricted with norepinephrine (NE) were observed by using tissue organ bath system. After pulmonary arterial rings were pretreated with three methods: removing the endothelium, pretreating with nitric oxide synthase inhibitor L-NAME or soluble guanylatecyclase inhibitor ODQ, the different effect of apelin was observed. In addition, the difference of vasodilatation between hypoxic rats and normal rats were observed.</p><p><b>RESULTS</b>(1) Exposure of intact endothelium pulmonary arterial rings preconstricted by NE to apelin at concentration (0.01 - 100 nmol/L) induced a significant concentration dependent relaxation. The maximal vasorelaxant effect of apelin was 10.62% +/- 2.60%, which was inhibited by removal of the endothelium (P < 0.01), pretreatment with L-NAME (P < 0.01) or ODQ (P < 0.01). (2) Response of pulmonary arterial rings from hypoxic pulmonary hypertension rats was decreased (P < 0.05). Compared to normal rats, at a concentration of 100 nmol/L, the response to apelin on arteries from hypoxic rats decreased 60.45% (P < 0.01). But the values of EC50 were not significantly different (P > 0.05).</p><p><b>CONCLUSION</b>These results indicate that apelin relaxes the pulmonary arterial rings of rats in an endothelium dependent manner, which may have a relationship to NO signaling pathway. The response of vasodilatation is decreased in the pulmonary arterial rings from the hypoxic rats.</p>

Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Apoptosis 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.</p><p><b>METHODS</b>Apelin 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).</p><p><b>RESULTS</b>Apelin 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.</p><p><b>CONCLUSIONS</b>The 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.</p>

Association of apelin genetic variants with type 2 diabetes and related clinical features in Chinese Hans / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Apelin is an adipokine that contributes to the pathogenesis of type 2 diabetes. The plasma levels of apelin increased in obese patients and diabetic subjects. This study aimed to investigate the effects of apelin genetic variants on type 2 diabetes and related quantitative traits.</p><p><b>METHODS</b>We selected three single nucleotide polymorphisms (SNPs) that could capture all common variants in APLN gene region and genotyped them in 1892 type 2 diabetic patients and 1808 normal glucose regulation controls. The clinical features related to glucose metabolism were measured in the controls. The comparison of allele and genotype distribution in the cases and controls were performed by using chi(2) tests. The association between SNPs and quantitative traits were analyzed using Wilcoxon's rank-sum test.</p><p><b>RESULTS</b>None of the SNPs or haplotypes showed evidence of association to type 2 diabetes. However, rs2235306 was nominally associated with fasting plasma glucose levels in the male subjects with normal glucose regulation ((4.93 +/- 0.03) vs (5.01 +/- 0.03) mmol/L, P = 0.04). No significant difference was observed between all three SNPs and other variables.</p><p><b>CONCLUSIONS</b>APLN SNP rs2235306 was associated with fasting plasma glucose levels in males. It suggests that APLN genetic variants may contribute to clinical features related to glucose metabolism in Chinese population.</p>

Effects of puerarin on expression of apelin and its receptor of 2K1C renal hypertension rats / 中国中药杂志

<p><b>OBJECTIVE</b>To examine the change of puerarin on the expression of apelin and its receptor of the two-kidney, one-clip (2K1C) rats.</p><p><b>METHOD</b>Tirty male Sprague-Dawley rats were randomly divided into normal control group (C), model group (M) and puerarin group (P). The mean of carotid arterial pressure (mCAP), mean of left ventricular end diastolic pressure (LVEDP), and the weight ratio of left ventricular mass (left ventricle plus septum) to bodyweight (LVM/BW) were measured to evaluate the model of 2K1C renal hypertension. The concentrations of apelin in the plasma and left ventricle (LV) were measured with radioimmunoassay. Apelin mRNA and APJ mRNA expressed in the LV were examined by reverse transcription-polymerase chain reaction (RT-PCR). The peptides of apelin and APJ expressed in the LV were detected with immunohistochemistry (IHC).</p><p><b>RESULT</b>Compared with C group, the mCAP, LVEDP and LVM/BW of M group were higher 36.58%, 333.8% and 20.24%, respectively (P<0.05, P<0.01, P<0.01). Compared with M group, LVEDP and LVM/BW of P group were lower 65.24% and 13.12%, respectively (both P<0.05). However mCAP was of no significant difference between these two groups. The levels of apelin-36 in the plasma and LV of M group were respectively higher 18.56% and 207.38% than those of C group (both P<0.05), while ones of P group were lower 24.21% and 49.40% than those of M group (both P<0.05). The expressions of apelin mRNA and APJ mRNA at left ventricle tissues of 2K1C rats were higher 77.66% and 119.00% (both P<0.05) than those of C group. The ones of P group were lower 27.40% and 45.66% than those of M group (both P<0.01). The IHC results indicate that the expressions of apelin and APJ peptides at left ventricle tissues of 2K1C rats were higher 129.51% and 154.1% (both P<0.01) than those of C group, respectively. Whereas the ones of P group were lower 65.36% and 62.87% than those of M group (both P<0.01).</p><p><b>CONCLUSION</b>Through regulating apelin/APJ system puerarin has protective effect on the development of left ventricular hypertrophy by renal hypertension.</p>

Changes and clinical significance of serum Apelin in patients with severe sepsis and septic shock / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the changes and clinical significance of serum Apelin in patients with severe sepsis and septic shock.</p><p><b>METHOD</b>We measured the serum level of Apelin with ELISA on different observation days (the 1st, 3rd, and 10th day obtaining the diagnosis) in 26 patients with severe sepsis and septic shock.</p><p><b>RESULTS</b>Serum Apelin significantly increased in sepsis patients when compared with the normal control group (P<0.01); The serum Apelin levels significantly changed among different observation days (P< 0.01). Serum Apelin level was significantly higher in patients with septic shock than those with severe sepsis (P<0.01).</p><p><b>CONCLUSION</b>Serum Apelin level changes in patients with severe sepsis and septic shock, which may provide clues in diagnosis and prognosis.</p>