Apelin/APJ 系统对能量代谢及其相关疾病调控的影响

G蛋白偶联受体APJ及其内源性配体Apelin在许多外周组织和中枢神经系统中高度表达,包括骨骼肌、胰腺、脂肪组织和下丘脑。Apelin /APJ系统调控许多生理功能,如调节血管生成,液体体内平衡和能量代谢;同时还参与不同疾病的发生发展,如糖尿病及其并发症、肥胖等。越来越多的证据表明,Apelin/APJ系统能调节胰岛素敏感性,刺激葡萄糖利用缓解糖尿病的形成;Apelin/APJ系统还能缓解肥胖引起的高血压、心血管等疾病;同时Apelin/APJ系统能促进肿瘤细胞的增殖与迁移。这篇综述旨在介绍Apelin /APJ系统在人体内各组织中可能存在的能量代谢调节功能及其对相关代谢性疾病的调控,Apelin /APJ系统有望成为潜在的用于治疗代谢性疾病的分子靶标。     

Apelin/APJ系统-能量代谢调控的重要靶点

脂肪组织不仅储存能量,更可通过分泌多种脂肪因子调节胰岛素的敏感性和能量代谢平衡。Apelin是由脂肪组织产生和分泌的一类新型脂肪因子,其受体为血管紧张素1型受体(APJ),为G蛋白偶联受体家族的成员之一。迄今为止,apelin是APJ的唯一天然内源性配体。研究证明,apelin与心血管功能、内分泌调节、食物摄入、细胞增殖、免疫调节、体液平衡和血管生成密切相关。且apelin可以通过内分泌、旁分泌、自分泌等方式作用于不同组织,从而参与肥胖及相关疾病的发生与发展。本文对近年来apelin在各类组织中的能量代谢调节作用及信号通路等方面的研究进行了归纳,并对apelin/APJ系统在治疗代谢紊乱疾病等的前景进行了展望。     

Apelin——肿瘤血管异生的有效激活剂

Apelin是1998年发现的孤儿G蛋白偶联受体APJ(又称为血管紧张素Ⅱ受体样受体1)的内源性配体,其前体由77个氨基酸残基组成,剪切后生成具有生物活性的apelin。Apelin具有调节血压、心脏收缩力、免疫反应、饮水和摄食的作用。Sorli SC等先前已经证明apelin能够促进内皮细胞有丝分裂     

Apelin及其生物学效应

Apelin是Tatemoto等利用反向药理学方法从牛胃分泌物中提取并纯化出的孤儿G蛋白偶联受体——血管紧张素受体AT1相关的受体蛋白(putativereceptorproteinrelatedtotheangiotensinreceptorAT1,APJ)的天然配体。Apelin及其受体APJ在体内分布广泛,以内分泌、旁/自分泌的方式调节心血管系统稳态、水盐平衡等,是一种重要的生理调节肽。有意义的是,Apelin还是一种免疫调节肽,可通过与其受体APJ结合抵抗病毒的入侵,抑制淋巴细胞胆碱能活性,参与免疫缺陷疾病和获得性免疫缺陷综合征(acquiredimmunedeficiencysyndrome,AIDS)免疫反应,调节免疫炎症因子生成,在调节免疫反应中起一定作用。作为心血管活性肽Apelin具有扩张血管、降低血压和增强心肌收缩力的效应;心血管疾病中,Apelin及其受体APJ均有不同程度的变化,在心力衰竭及心肌重塑中具有重要调节意义。     

Apelin/APJ系统的神经保护作用及其机制

Apelin/APJ系统在人与动物组织中广泛分布,不仅参与维持生理稳态,也参与多种疾病的病理生理过程。越来越多的证据表明,apelin/APJ系统具有神经保护作用,能对抗兴奋性毒性损伤、氧化应激损伤以及损伤诱导的神经元凋亡。本文现就apelin/APJ系统神经保护作用及其机制的相关研究进展作一综述。     

肥胖时过表达的新的脂肪因子apelin：是友是敌？

Apelin是孤儿G蛋白偶联受体一血管紧张素受体AT1相关的受体蛋白（putative receptor protein related to the angiotensin receptor AT1,AH）的天然配体。Apelin及其受体APJ在体内分布广泛。Boucher等报道在分离出的人及小鼠成熟脂肪细胞有apelin的合成和分泌,并认为apelin是一种新的脂肪因子。     

Apelin与心血管疾病

Apelin(APJ endogenous ligand)蛋白是孤儿G蛋白偶联受体-血管紧张素Ⅱ1型受体相关蛋白(receptor protein related to the angiotensin-Ⅱprotein one,APJ)独特的内源性配体。Apelin/APJ系统在机体内广泛分布,包括心血管系统,它具有正性肌力、扩张外周血管、抑制细胞肥大和保护缺血心肌等多种重要的生物学功能。现就Apelin/APJ结构分布及其在心血管疾病中的相关研究做一综述。     

Apelin 在心血管疾病中的研究进展

Apelin是APJ(angiotensin II protein J)的一个配体,是一种重要的生理调节肽。Apelin-APJ系统在心血管系统存在广泛的作用,参与高血压、冠心病、心力衰竭及心房纤颤等多种疾病的病理生理过程,本文就apelin的生物学特性及与多种心血管疾病的关系作一综述。     

游泳运动对低氧性肺动脉高压大鼠肺组织apelin及其受体表达的影响

目的:探讨游泳运动对大鼠肺组织新的小分子活性肽apelin及其受体(APJ)表达的影响。方法:45只雄性大鼠随机分成三组:正常对照组、低氧组(七周)和游泳组(低氧+游泳锻炼七周组,低氧3周后,于每天入低氧舱前行无负重游泳运动60 min,每天1次)。七周后测定各组大鼠平均肺动脉压(mPAP)、右心室与左心室加室间隔的重量比[RV/(LV+S)]、肺细小动脉管壁面积/管总面积(WA/TA)、管腔面积/管总面积(CA/TA)及中膜厚度(PAMT)。免疫蛋白印迹与免疫组化法测定肺组织apelin/APJ的蛋白表达。结果:①低氧组mPAP和RV/(LV+S)比正常对照组分别高73.6%和31.2%(P均<0.01),而游泳组比低氧组分别低21.1%和8.9%(P均<0.05)。②低氧组WA/TA和PAMT较正常对照组分别高70.8%和102%,而游泳组较低氧组分别低24.8%和40.1%(P均<0.01)。低氧组CA/TA较正常对照组低15.1%,而游泳组较低氧组高10.3%(P均<0.01)。③低氧组肺组织apelin蛋白表达较正常对照组上调374%(P<0.01),而APJ蛋白表达下调87.1%(P均<0.01);游泳组肺组织apelin蛋白表达较低氧组下调48%,而APJ蛋白表达上调287%(P均<0.01)。④apelin蛋白主要在血管外膜及炎症细胞胞浆内表达,APJ蛋白主要在血管内膜、外膜及炎症细胞上表达。结论:游泳运动减缓肺动脉高压和肺血管重塑作用可能与调节肺组织apelin/APJ系统的表达有关。     

PI3K信号通路介导apelin-13促进单核细胞-血管内皮细胞黏附的研究

本室以前已经报道G蛋白偶联受体APJ的内源性配体多肽apelin-13促进单核细胞-血管内皮细胞黏附,本文研究PI3K信号途径是否参与apelin-13促进单核细胞-血管内皮细胞黏附,探讨apelin/APJ系统的细胞信号转导机制.MPO方法检测细胞黏附;Western blot方法检测PI3K、VCAM-1的表达.Western blot方法结果显示,apelin-13(0、0.5、1、2、4μmol/L)浓度依赖性刺激血管内皮细胞PI3K磷酸化,以1μmol/L最为明显;1μmol/L apelin-13时间依赖性促进血管内皮细胞PI3K磷酸化,在30 min增加最为显著;PI3K抑制剂LY294002明显抑制apelin-13诱导的VCAM-1表达和单核细胞-血管内皮细胞黏附.上述结果表明,PI3K信号途径介导apelin-13促进单核细胞-血管内皮细胞黏附.     

Apelin/APJ system: a promising therapy target for hypertension

Apelin is a recently described endogenous peptide and its receptor APJ, is a member of the G protein-coupled receptors family. Apelin and APJ are widely distributed in central and peripheral tissues exert important biological effects on cardiovascular system. Recent studies have suggested that apelin/APJ system involves in decreasing the blood pressure and have a close relationship with hypertension, presumably, pathophysiology of hypertension as well. Such as, apelin/APJ system may be concerned in hyperfunction of the sympathetic nervous system, renin–angiotensin–aldosterone system, endothelial injury, excessive endothelin, sodium retention, vascular remodeling, insulin resistance elicit hypertension, as well as in hypertension-induced organ damaged. Meanwhile, on the ground of the variation of apelin level in hypertension therapeutic process and combining with the recently researches on APJ agonist and antagonist, we could infer that apelin/APJ system would be a promising therapeutic target for hypertension and other cardiovascular disease in the future. However, the role of apelin on these pathogenic conditions was not consistent, consequently, the contradictory role of apelin on these pathogenesis of hypertension would be discussed in this article.     

Function and regulation of apelin/APJ system in digestive physiology and pathology

Apelin is an endogenous ligand of seven-transmembrane G-protein-coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, liver, kidney, and gastrointestinal tract and even in tumor tissues. Studies show that apelin messenger RNA is widely expressed in gastrointestinal (GI) tissues, including stomach and small intestine, which is closely correlated with GI function. Thus, the apelin/APJ system may exert a broad range of activities in the digestive system. In this paper, we review the role of the apelin/APJ system in the digestive system in physiological conditions, such as gastric acid secretion, control of appetite and food intake, cell proliferation, cholecystokinin secretion and histamine release, gut–brain axis, GI motility, and others. In pathological conditions, the apelin/APJ system plays an important role in the healing process of stress gastric injury, the clinical features and prognosis of patients with gastric cancers, the reduction of inflammatory response to enteritis and pancreatitis, the mediation of liver fibrogenesis, the promotion of liver damage, the inhibition of liver regeneration, the contribution of splanchnic neovascularization in portal hypertension, the treatment of colon cancer, and GI oxidative damage. Overall, the apelin/APJ system plays diversified functions and regulatory roles in digestive physiology and pathology. Further exploration of the relationship between the apelin/APJ system and the digestive system will help to find new and effective drugs for treating and alleviating the pain of digestive diseases.     

Apelin suppresses apoptosis of human vascular smooth muscle cells via APJ/PI3-K/Akt signaling pathways

Apoptosis of vascular smooth muscle cells (VSMCs) plays an important role in regulating vascular remodeling during cardiovascular diseases. Apelin is the endogenous ligand for the G-protein-coupled receptor APJ and plays an important role in the cardiovascular system. However, the mechanisms of apelin on apoptosis of VSMCs have not been elucidated. Using a culture of human VSMCs as a model for the study of apoptosis, the relationship between apelin and apoptosis of human VSMCs and the signal pathway involved were investigated. Using western blotting, we confirmed that VSMCs could express APJ. To evaluate the possible role of apelin in VSMC apoptosis, we assessed its effect on apoptosis of human VSMCs. The results showed that apelin inhibited human VSMCs apoptosis induced by serum deprivation. Suppression of APJ with small-interfering RNA (siRNA) abolished the anti-apoptotic activity of apelin. Apelin increased Bcl-2 protein expression, but decreased Bax protein expression. An increase in activation of extracellular signal-regulated protein kinase (ERK) and Akt (a downstream effector of phosphatidylinositol 3-kinase) was shown after apelin stimulation. Suppression of APJ with siRNA abolished the apelin-induced activation of ERK and Akt. LY294002 (a PI3-K inhibitor) blocked apelin-induced activation of Akt and abolished the apelin-induced antiapoptotic activity. Our study suggests that apelin suppresses serum deprivation-induced apoptosis of human VSMCs, and that the anti-apoptotic action is mediated through the APJ/PI3-K/Akt signaling pathways.     

Biology of the apelin-APJ axis in vascular formation

Apelin is a bioactive peptide with diverse physiological actions on many tissues mediated by its interaction with its specific receptor APJ. Since the identification of apelin and APJ in 1998, pleiotropic roles of the apelin/APJ system have been elucidated in different tissues and organs, including modulation of the cardiovascular system, fluid homeostasis, metabolic pathway and vascular formation. In blood vessels, apelin and APJ expression are spatiotemporally regulated in endothelial cells (ECs) during angiogenesis. In vitro analysis revealed that the apelin/APJ system regulates angiogenesis by the induction of proliferation, migration and cord formation of cultured ECs. Moreover, apelin seems to stabilize cell-cell junctions of ECs. In addition, genetically engineered mouse models suggest that apelin/APJ regulates vascular stabilization and maturation in physiological and pathological angiogenesis. In this review, we summarize the current understanding of the apelin/APJ system for vascular formation and maturation.     

Apelin and its receptor are expressed in human osteoblasts

OBJECTIVES: Apelin is a recently discovered peptide that is the endogenous ligand for the orphan G-protein-coupled receptor APJ. Adipocytes can express and secrete apelin. The aim of this study was to characterize apelin and APJ expression in human osteoblasts and to investigate the effects of apelin on osteoblasts. RESULTS: Apelin and APJ were expressed in human osteoblasts. Apelin stimulated proliferation of human osteoblasts, but had no effect on alkaline phosphatase (ALP) activity, osteocalcin and type I collagen production in human osteoblasts. Suppression of APJ with small-interfering RNA (siRNA) abolished the apelin-induced cell proliferation. Apelin induced activation of Akt (Phosphatidylinositol-3 kinase downstream effector), but not MAPKs, such as c-jun N-terminal Kinase (JNK), p38 and ERK1/2 in human osteoblasts. This effect was blocked by suppression of APJ with siRNA. Furthermore, LY294002 (PI3 kinase inhibitor) blocked the activation of Akt by apelin and abolished the apelin-induced cell proliferation. CONCLUSIONS: Human osteoblasts express apelin and APJ and apelin enhances human osteoblast proliferation, but has no effect on osteoblast differentiation, and APJ/PI3 kinase/Akt pathway is involved in the proliferation response. These findings suggest that apelin may function as a mitogenic agent for osteoblasts.     

Apelin/APJ system: A potential therapeutic target for endothelial dysfunction-related diseases

APJ is a G protein-coupled receptor and its endogenous ligand is apelin. Studies have shown that apelin/APJ system is widely distributed in the body, especially highly expressed in the vascular endothelial cells (ECs). Numerous reports have demonstrated that apelin/APJ system plays an important role in the regulation of ECs function. Our lab has demonstrated that apelin-13 is able to promote adhesion of monocyte-human umbilical vein EC via 14-3-3, and reactive oxygen species-autophagy signaling pathways. In this review, we concentrate on the regulatory mechanism of apelin/APJ system in EC, including promotion of proliferation, migration, and angiogenesis. Moreover, we also analyze the role of apelin/APJ on endothelial dysfunction-related diseases including atherosclerosis, diabetes, hypertension, and myocardial infarction. Finally, we summarize the most commonly used agonists and antagonists of APJ. Therefore, apelin/APJ system is expected to be a therapeutic target for the treatment of endothelial dysfunction-related diseases.     

Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats

Because apelin may play an important regulatory role in human cardiac dysfunction, we investigated alterations in cardiovascular content of apelin and its receptor, APJ, during hypertension and the effect of exercise training on the cardiovascular apelin/APJ system in hypertensive animals. Spontaneously hypertensive rats (SHRs) underwent swimming training consisting of 54 swimming sessions of 60 min each (6 days/week for 9 weeks). Systolic blood pressure (SBP) was verified weekly by tail-cuff plethysmography. Apelin levels in plasma and cardiovascular tissues were determined by radioimmunoassay. The level of apelin/APJ mRNA was determined by RT-PCR. SHRs showed severe hypertension and pathological cardiomegaly. The level of apelin immunoreactivity (apelin-ir) in plasma and ventricular and aortic tissues was lower, by 40%, 40% and 42% (all P<0.01), respectively, in SHRs than in control Wistar-Kyoto rats, and the mRNA level of apelin and APJ in myocardium and aorta was markedly decreased. Compared with sedentary SHRs, swimming-trained SHRs showed decreased SBP and elevated mRNA expression of apelin and APJ in cardiovascular tissues and elevated apelin-ir level in plasma, myocardium and aorta (all P<0.01). SBP and level of apelin-ir in plasma and cardiovascular tissues were negatively correlated. Long-term swimming training relieved the pathogenesis of hypertension and reversed the downregulation of the cardiovascular apelin/APJ system induced by hypertension, which suggests that the improving effect of exercise training on hypertension could be mediated by upregulating the cardiovascular apelin/APJ system.