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。     

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 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。     

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：血管功能调节因子和药物治疗新靶点

Apelin(APJendogenousligand)是血管紧张素Ⅱ1型受体相关蛋白(angiotensin receptor-like 1,APJ)的内源性配体.Apelin/APJ系统在机体内广泛分布,在众多血管系统表达水平较高,如心血管系统、肺血管系统等.研究发现,apelin可调节血管张力,促进血管平滑肌细胞增殖、视网膜血管新生以及单核细胞向内皮细胞黏附,促进肝门静脉和冠状动脉侧枝形成等.本文就apelin调节血管功能及其相关疾病(高血压、肺动脉高压、动脉粥样硬化、胶质瘤、肺癌、门静脉高压、糖尿病血管并发症等)进行综述,揭示了apelin与血管及其相关疾病的内在联系,表明apelin/APJ可作为血管疾病的治疗靶点.     

IL-6促进小鼠胚胎干细胞多能性并以发育依赖的方式调控心肌分化（英文）

白细胞介素6 (interleukin 6, IL-6)是心脏微环境的重要组成部分。在不同模型中,IL-6通过促进心肌细胞再生帮助心脏修复。胚胎干细胞是心脏修复中心肌再生的良好来源。本研究旨在探讨IL-6对小鼠胚胎干细胞(mouse embryonic stem cells,mESCs)及其心肌分化的影响。IL-6处理mESCs两天,用CCK-8法检测mESCs增殖情况,用实时荧光定量PCR(quantitative real-time PCR, qPCR)检测干性和胚层分化基因mRNA表达水平,用Western blot检测干细胞相关信号通路的磷酸化水平,用siRNA干扰STAT3磷酸化功能。通过检测搏动拟胚体(embryoid bodies, EBs)比例和qPCR检测心脏前体细胞标记物和心肌细胞离子通道mRNA表达水平来评估mESCs的分化能力。从胚胎干细胞分化第1天(EB0)开始使用IL-6中和抗体阻断内源性IL-6的作用,分别在EB7、EB10和EB15检测心肌细胞分化;在EB15用免疫组织化学染色法示踪心肌细胞,并用Western blot检测干细胞相关信号通路的磷酸化情况...     

增殖分化视角下成年哺乳动物心肌再生研究进展

心肌再生是逆转心肌损伤和心力衰竭的理想途径,也是心血管医学领域的研究重点。传统观点认为成年哺乳动物心肌细胞无法自我更新和再生,然而最近研究报道心肌细胞能以微弱比例内源再生。通过调节心肌再生过程或调控关键分子表达,可以诱导具有收缩功能的心肌细胞出现,改善损伤心脏的结构和功能。近年心肌再生研究大多侧重细胞增殖,对心肌细胞去分化、增殖及再分化的全过程关注较少。因此,该文从增殖分化视角综述成年哺乳动物心肌再生的诱导方式,旨在探讨实现成年哺乳动物心肌细胞大规模自我更新的可能性。     

Apelin receptor(APJ)拮抗剂F13A对小鼠抑郁样行为的影响及起效时间*

目的:明确apelin receptor(APJ)拮抗剂F13A对小鼠抑郁样行为的影响及起效时间。方法:实验小鼠随机分成对照组(Control),F13A组(F13A)和氯胺酮组(ketamine),每组9只,对照组小鼠腹腔注射生理盐水(10 ml/kg,ip)+侧脑室注射生理盐水(每职1μl,i.c.v),F13A组小鼠腹腔注射生理盐水(10 ml/kg,ip)+侧脑室注射F13A(6 μg/μl,i.c.v),氯胺酮组小鼠腹腔注射氯胺酮(10 ml/kg, 2 mg/ml,ip)+侧脑室注射生理盐水(1μl,i.c.v);实验分三批进行,第一批实验在注射后30 min,进行第一次强迫游泳测试(FST1),FST1后24 h进行第二次强迫游泳测试(FST2);第二批实验在注射后30 min进行第一次自发活动测试(LMT1),LMT1前24 h进行自发活动习惯化,LMT1后24 h进行第二次自发活动测试(LMT2);第三批实验注射后30 min进行FST1,FST1前24 h进行强迫游泳应激(FSS),FST1后24 h进行第二次强迫游泳测试(FST2)。 结果:与对照组比较,在无FSS时,氯胺酮组小鼠不动时间显著性减少(P﹤0.01),而F13A组小鼠无明显变化;在FST2中,F13A组小鼠不动时间显著性增加(P﹤0.01),而氯胺酮组小鼠无显著性差异;在LMT1和LMT2中各组小鼠活动度均无显著性差异;在经历FSS后,在FST1中氯胺酮组、F13A组小鼠不动时间均显著性减少(P﹤0.01);在FST2中,F13A组小鼠的不动时间显著性减少(P﹤0.05),而氯胺酮组小鼠无显著性差异(P＞0.05)。结论:APJ受体拮抗剂F13A在强迫游泳测试中发挥快速起效(30 min)且持久作用(24 h)的抗抑郁样潜力,并且这种作用可能与应激有关。     

Apelin/APJ调节鱼类摄食的研究进展

Apelin是1998年首次从牛胃分泌物中提取出的APJ的内源性配体,Apelin及其受体APJ广泛分布于动物中枢和外周组织中。Apelin通过与受体APJ结合,不仅参与血压调节、痛觉调节、体液平衡和细胞凋亡等多种生理过程,还在动物摄食调控和胃肠道运动调节中发挥重要作用。目前,关于Apelin调控摄食的作用还存在争议。现依据Apelin和APJ在哺乳动物和鱼类的研究进展,阐述Apelin及APJ的结构、组织分布和对动物摄食的调控及其机制,以期为其在鱼类摄食调控方面的研究提供参考。     

雷帕霉素促进胚胎干细胞向心肌细胞分化

目的 雷帕霉素是小分子mTOR抑制剂,可激活细胞自噬.本研究检测了雷帕霉素对胚胎干细胞(ES细胞)向心肌分化的影响.方法 采用拟胚体(embryoid body,EB)加抗坏血酸诱导ES细胞向心肌分化.悬浮诱导阶段添加自噬激动剂雷帕霉素或抑制剂羟氯喹,通过免疫印迹检测LC3蛋白剪切以监测细胞自噬水平,通过检测EB球的心...     

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.     

Circulating and cardiac levels of apelin,the novel ligand of the orphan receptor APJ,in patients with heart failure

The orphan receptor APJ and its recently identified endogenous ligand, apelin, are expressed in the heart. However, their importance in the human cardiovascular system is not known. This study shows that apelin-like immunoreactivity is abundantly present in healthy human heart and plasma. Gel filtration HPLC analysis revealed that atrial and plasma levels of high molecular weight apelin, possibly proapelin, were markedly higher than those of mature apelin-36 itself. As assessed by quantitative RT-PCR analysis, left ventricular apelin mRNA levels were increased 4.7-fold in chronic heart failure (CHF) due to coronary heart disease (p<0.01) and 3.3-fold due to idiopathic dilated cardiomyopathy (p<0.05), whereas atrial apelin mRNA levels were unchanged. Atrial and plasma apelin-like immunoreactivity as well as atrial and ventricular APJ receptor mRNA levels were significantly decreased in CHF. Our results suggest that a new cardiac regulatory peptide, apelin, and APJ receptor may contribute to the pathophysiology of human CHF.     

The apelinergic system in the developing lung: expression and signaling

Apelin and its receptor APJ constitute a signaling pathway best recognized as an important regulator of cardiovascular homeostasis. This multifunctional peptidergic system is currently being described to be involved in embryonic events which extend into vascular, ocular and heart development. Additionally, it is highly expressed in pulmonary tissue. Therefore, the aim of this study was to investigate the role of apelinergic system during fetal lung development. Immunohistochemistry and Western blot analysis were used to characterize apelin and APJ expression levels and cellular localization in normal fetal rat lungs, at five different gestational ages as well as in the adult. Fetal rat lung explants were cultured in vitro with increasing doses of apelin. Treated lung explants were morphometrically analyzed and assessed for MAPK signaling modifications. Both components of the apelinergic system are constitutively expressed in the developing lung, with APJ exhibiting monomeric, dimeric and oligomeric forms in the pulmonary tissue. Pulmonary epithelium also displayed constitutive nuclear localization of the receptor. Fetal apelin expression is higher than adult expression. Apelin supplementation inhibitory effect on branching morphogenesis was associated with a dose dependent decrease in p38 and JNK phosphorylation. The results presented provide the first evidence of the presence of an apelinergic system operating in the developing lung. Our findings also suggest that apelin inhibits fetal lung growth by suppressing p38 and JNK signaling pathways.     

Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression

Apelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy. Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis. Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750±133500 vs. 901600±143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0±4.6 vs. 1.0±1.2 ng/ml, n=5, p=0.006) and western blot (1579400±477733 vs. 943000±157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.     

Neuroprotection of apelin and its signaling pathway

Apelin was initially isolated from bovine stomach and is an endogenous neuropeptide. It is a native ligand of the apelin receptor (APJ). Some research has found that apelin peptides alter blood pressure, feeding behavior, and pituitary hormone release. However, a new neuroprotective effect of apelin peptides was only recently discovered. This review summarizes the evidence of apelin-neuroprotection, which has the potential to cure acute and chronic neurological diseases.     

葛根素对人非小细胞肺癌A549细胞凋亡的作用

目的：观察葛根素对人非小细胞肺癌A549细胞生长的抑制作用及其机制。方法：体外培养人非小细胞肺癌细胞（A549）,不同浓度（60 μg/ml,120 μg/ml,240 μg/ml）葛根素处理24 h后;采用CCK-8法观察葛根素对细胞的增值抑制作用;吖啶橙（AO）/溴化乙锭（EB）双染法及AnnexinⅤ-PI双染流式细胞术检测药物作用前后A549细胞的形态学变化及凋亡状况;Western blot法检测Apelin/APJ蛋白水平的变化。结果：CCK-8法检测结果说明葛根素能抑制A549细胞的增值,具有浓度和时间依赖关系;流式细胞术进一步证实葛根素具有诱导细胞凋亡的作用,与A549细胞组比较,葛根素各处理组Apelin/APJ蛋白水平均有不同程度下调。结论：葛根素可能通过调节Apelin/APJ蛋白的表达诱导A549细胞凋亡。