Discovery of a Competitive Apelin Receptor (APJ) Antagonist

Macaluso, N. J. Maximilian; Pitkin, Sarah L.; Maguire, Janet J.; Davenport, Anthony P.; Glen, Robert C.

doi:10.1002/cmdc.201100069

Cited by 62 publications

(62 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The inhibitory effect of apelin on platelet aggregation involves the APJ receptor Using 2 APJ antagonists, apelin-F13A (F13A) 23 and MM54, 24 we found that F13A or MM54 alone did not significantly modify platelet aggregation. In contrast, inhibition of platelet aggregation by apelin-13 was completely prevented by F13A and partially prevented by MM54 ( Figure 1F).…”

Section: Resultsmentioning

confidence: 89%

Apelin: an antithrombotic factor that inhibits platelet function

Adam

Khatib

López

et al. 2016

Blood

View full text Add to dashboard Cite

Key Points• Apelin plays a key role in maintaining hemostasis through the regulation of platelet function.• Treatment of platelets with apelin inhibits aggregation and thrombus formation.Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin-and collagenmediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile. Their platelets exhibited increased adhesion and a reduced occlusion time in venules, and displayed a higher aggregation rate after their activation by thrombin compared with wild-type platelets. Consequently, human and mouse platelets express apelin and its receptor APJ. Apelin directly interferes with thrombin-mediated signaling pathways and platelet activation, secretion, and aggregation, but not with ADP and thromboxane A 2 -mediated pathways. IV apelin administration induced excessive bleeding and prevented thrombosis in mice. Taken together, these findings suggest that apelin and/or APJ agonists could potentially be useful adducts in antiplatelet therapies and may provide a promising perspective for patients who continue to display adverse thrombotic events with current antiplatelet therapies. (Blood. 2016;127(7):908-920)

show abstract

Section: Resultsmentioning

confidence: 89%

Apelin: an antithrombotic factor that inhibits platelet function

Adam

Khatib

López

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…In a study carried out to understand the molecular features of apelin required for a signalling response from APJ, three cyclic analogues of apelin-12 (C1, C3 and C4) have proved to be novel APJ agonists, but are less potent than (Pyr 1 )apelin-13 in the inhibition of cAMP accumulation and in the phosphorylation of protein kinase B (Akt) and ERK1/2 (Hamada et al 2008), while the use of a bivalent ligand approach incorporating a b-turn within the RPRL region of apelin, which is critical in APJ ligand recognition, has resulted in the identification of a competitive antagonist at APJ (Macaluso et al 2011).…”

Section: Cyclic and Other Apelin Analoguesmentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

292

216

View full text Add to dashboard Cite

The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

show abstract

“…Compellingly, the conserved structural features of the apelin isoforms have been directly employed in design of peptide-based AR antagonists (Macaluso and Glen 2010;Macaluso et al 2011), and agonists (Murza et al 2012). Despite the clear importance of the apelin C-terminal dodecapeptide region, the presence of multiple apelin isoforms in the body suggests an evolutionary purpose.…”

Section: Apelin-induced Signallingmentioning

confidence: 99%

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

Chapman

Dupré

Rainey

2014

Biochem. Cell Biol.

176

135

View full text Add to dashboard Cite

The apelin receptor (AR or APJ) is a class A (rhodopsin-like) G-protein coupled receptor (GPCR) with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, apelin, induces diverse physiological effects including vasoconstriction and dilation; strengthening of heart muscle contractility; angiogenesis; and, regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ ELABELA, was identified as having a crucial role in zebrafish embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about mechanisms of peptide-AR activation. Additional complexity arises from modulation of the AR by two endogenous peptide ligands, both with multiple bioactive isoforms of variable length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other GPCRs. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR.

show abstract

Discovery of a Competitive Apelin Receptor (APJ) Antagonist

Cited by 62 publications

References 50 publications

Apelin: an antithrombotic factor that inhibits platelet function

Apelin: an antithrombotic factor that inhibits platelet function

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

Contact Info

Product

Resources

About