Disease relevance of APLN

• These studies demonstrate the ability of a small peptide ligand to block the function of APJ as an HIV-1 coreceptor, identify apelin sequences important for the inhibition, and provide new reagents for the investigation of the significance of APJ to HIV-1 infection and pathogenesis [1].
• Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ, inhibits human immunodeficiency virus type 1 entry [1].
• We additionally extend the clinical significance of this work by reporting for the first time circulating human apelin levels and demonstrating increases in the plasma level of apelin in patients with left ventricular dysfunction [2].
• Apelin, a newly identified adipokine up-regulated by insulin and obesity [3].
• 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 [4].

Psychiatry related information on APLN

• Intraperitoneal apelin injections induced an increase in drinking behavior within the first 30 min after injection, with a return to baseline within 1 h [5].
• Hypothesis-testing abilities were assessed using a modification of the discrimination-learning paradigm employed by Nelson, Kamhi, and Apel (1987) that was designed to minimize the short-term memory demands of the task [6].

High impact information on APLN

• Now, roles have been established for the apelin system in lowering blood pressure, as a potent cardiac inotrope, in modulating pituitary hormone release and food and water intake, in stress activation, and as a novel adipokine that is excreted from fat cells and regulates insulin [7].
• Similarities between the structure and anatomical distribution of apelin and its receptor and that of angiotensin II and the angiotensin AT(1) receptor provide clues about the physiological functions of this novel signal-transduction system [7].
• Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity [7].
• Given its broad array of physiological roles, apelin has attracted much interest as a target for novel therapeutic research and drug design [7].
• Here, we investigated whether apelin interacts with arginine vasopressin (AVP) to maintain body fluid homeostasis [8].

Chemical compound and disease context of APLN

• We have shown recently that apelin and apelin receptor mRNA are expressed in brain and that the centrally injected apelin fragment K17F (Lys(1)-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe(17)) decreased vasopressin release and altered drinking behavior [9].

Biological context of APLN

• Suppression of APJ with small-interfering RNA (siRNA) abolished the apelin-induced cell proliferation [10].
• Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor [11].
• Apelin suppresses apoptosis of human osteoblasts [12].
• Together, our findings show that USF exerts a stimulatory role in regulation of breast apelin expression during pregnancy and lactation [13].
• Mutagenesis and overexpression assays showed that USF up-regulates basal and inducible apelin transcription [13].

Anatomical context of APLN

• Adipocytes can express and secrete apelin [10].
• Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells [14].
• Apelin and its receptor are expressed in human osteoblasts [10].
• Therefore, based on the presence of APJ and mRNA encoding apelin in human tissues, we investigated the expression of apelin in fresh-frozen human tissue from right atrium, left ventricle, lung, kidney, adrenal and large conduit vessels using immunocytochemistry [14].
• Apelin-LI does not co-localise with von Willebrand factor in Weibel-Palade bodies, suggesting synthesis of apelin via the constitutive pathway [15].

Associations of APLN with chemical compounds

• Antiviral potency was influenced by the integrity of methionine 75, which contributes to APJ-binding affinity, and by the retention of apelin residues 63 to 65 [1].
• In particular, we have identified that replacement of leucine in position 5, or arginine in position 2 and 4 of the C-terminal apelin peptide, apelin-13, resulted in significant changes in pharmacology [16].
• Furthermore, LY294002 (PI3 kinase inhibitor) blocked the activation of Akt by apelin and abolished the apelin-induced cell proliferation [10].
• Furthermore, apelin protects against apoptosis induced by the glucocorticoid dexamethasone [12].
• Both sequence and mRNA expression distribution analyses revealed similarities between apelin and angiotensin II, suggesting they that share related physiological roles [5].

Physical interactions of APLN

• CONCLUSIONS: Our findings of a significantly reduced peripheral level of apelin coupled with elevated AVP point to a subtle but definite vasopressinergic dysfunction in autism that could play a role in the etiopathophysiology of this disorder in humans [17].
• Among these, we identified genes and pathways already associated with renal dysfunction as well as a new subset of genes previously unknown to participate in this complication, including a G protein-coupled receptor that binds apelin, a protein phosphatase (calcineurin B) and a number of neuropeptide receptors and growth factors [18].

Regulatory relationships of APLN

• The apelin-induced activation of Akt was blocked by suppression of APJ with siRNA [12].
• Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells [19].
• The apelin receptor is a G protein-coupled receptor activated by several apelin fragments [20].

Other interactions of APLN

• The restricted presence of apelin-LI in endothelial cells suggests that endothelial apelin may play a role as a locally secreted cardiovascular mediator acting on APJ receptors present on the vascular smooth muscle and on cardiac myocytes to regulate vascular tone and cardiac contractility [14].
• Analysis of apelin analogues demonstrated that potent and specific antiviral activity was retained by a 13-residue, arginine-rich peptide [1].
• Agonist-independent nuclear localization of the Apelin, angiotensin AT1, and bradykinin B2 receptors [21].
• In response to agonist ligands both the orexin-1 and apelin receptors were able to rapidly translocate both beta-arrestin 1-GFP and beta-arrestin 2-GFP from cytoplasm to the plasma membrane [22].
• Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions [23].

Analytical, diagnostic and therapeutic context of APLN

• We demonstrate here using immunoassay and immunohistochemical techniques that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading [2].
• Northern and in situ hybridization analyses revealed both human and rat apelin and APJ to be expressed in the brain and periphery [5].
• 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 [4].
• The administration of apelin transiently decreased the blood pressure of wild-type mice and a hypertensive model animal, a spontaneously hypertensive rat [24].
• Confocal microscopy of HEK-293T cells revealed the majority of transfected cells displayed constitutive nuclear localization of AT(1) and B(2) receptors, whereas apelin receptors did not show nuclear localization in these cells [21].

References