Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity

https://doi.org/10.1016/j.tips.2006.02.006Get rights and content

The apelin receptor was initially classed as an orphan G-protein-coupled receptor, and little was known about its physiological functions until apelin, the endogenous ligand, was identified. Similarities between the structure and anatomical distribution of apelin and its receptor and that of angiotensin II and the angiotensin AT1 receptor provide clues about the physiological functions of this novel signal-transduction system. 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. Given its broad array of physiological roles, apelin has attracted much interest as a target for novel therapeutic research and drug design.

Section snippets

Characterization of the apelin system

The gene that encodes the apelin receptor (which was known previously as the APJ receptor) was discovered first by homology-cloning methods and it shares greatest sequence identity (54% in the transmembrane regions) with the angiotensin AT1 receptor [1]. Similar to many newly identified G-protein-coupled receptors (GPCRs), the absence of an immediately apparent endogenous ligand limited further characterization and, thus, the apelin receptor was added to a growing number of ‘orphan’ GPCRs that

A potent inotropic agent with cardioprotective properties

As predicted by the high levels of cardiovascular expression of apelin and its receptor and the well characterized role of angiotensin II on the circulatory system, the importance of apelin in modulating blood pressure and cardiac function is being revealed. For example, the density of apelin-binding sites in human and rat myocardium is comparable to that of the AT1 receptor [28]. When administered to isolated rat hearts, apelin is one of the most potent endogenous positive inotropic

Novel hypotensive action of apelin

Apelin modulates the contractility of blood vessels, which has the overall effect of lowering blood pressure. That apelin-13 regulates blood pressure was shown first following intravenous (i.v.) injection of 1 μg and 2 μg in anaesthetized rats, which resulted in a transient drop in mean arterial blood pressure (MABP) of ∼12 mmHg with no change in heart rate [5]. These results have been confirmed subsequently by studies in which injection of 10 nmol kg−1 apelin-12, apelin-13 and apelin-36 decreased

Apelin, obesity and the adipoinsular axis

The reported distribution of apelin and the apelin receptor in the hypothalamus, gastric mucosa and fat cells has led to the suggestion that the apelin system has roles in modulating appetite, digestion and metabolism following food intake. Whether apelin acts in the CNS to modulate feeding behaviour is controversial. Administration of apelin-13 by i.c.v., but not i.v., injection decreases food intake in both fed and starved rats [38]. Another report has observed similar effects when apelin is

Conclusions and future perspectives

Although the apelin receptor was discovered more than a decade ago, functional characterization of the apelin system began only recently following the identification of its endogenous ligands. Since its discovery as a mediator of the effects of the rennin–angiotensin system in 1940, the elucidation of the angiotensin system has revealed enormous complexity, with roles in diverse physiological mechanisms such as blood-pressure regulation, body-water balance, and hypothalamic functions documented

References (62)

  • C. Vickers

    Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase

    J. Biol. Chem.

    (2002)
  • Y. Habata

    Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum

    Biochim. Biophys. Acta

    (1999)
  • B. Masri

    Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein

    Biochem. Biophys. Res. Commun.

    (2002)
  • D.K. Lee

    Agonist-Independent nuclear localization of the apelin, angiotensin AT1 and bradykinin B2 receptors

    J. Biol. Chem.

    (2004)
  • G. Foldes

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

    Biochem. Biophys. Res. Commun.

    (2003)
  • M. Packer

    The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure

    J. Am. Coll. Cardiol.

    (1992)
  • J. Ishida

    Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo

    J. Biol. Chem.

    (2004)
  • K. Tatemoto

    The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism

    Regul. Pept.

    (2001)
  • X. Cheng

    Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats

    Eur. J. Pharmacol.

    (2003)
  • S. Kagiyama

    Central and peripheral cardiovascular actions of apelin in conscious rats

    Regul. Pept.

    (2005)
  • M. Seyedabadi

    Site-specific effects of apelin-13 in the rat medulla oblongata on arterial pressure and respiration

    Auton. Neurosci.

    (2002)
  • D. Sunter

    Intracerebroventricular injection of apelin-13 reduces food intake in the rat

    Neurosci. Lett.

    (2003)
  • S. Taheri

    The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats

    Biochem. Biophys. Res. Commun.

    (2002)
  • E. Susaki

    Apelin cells in the rat stomach

    Regul. Pept.

    (2005)
  • M.V. Heinonen

    Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding

    Regul. Pept.

    (2005)
  • M. Sorhede Winzell

    The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

    Regul. Pept.

    (2005)
  • L. Wei

    Regulation of apelin mRNA expression by insulin and glucocorticoids in mouse 3T3-L1 adipocytes

    Regul. Pept.

    (2005)
  • L.O. Lerman

    Animal models of hypertension: an overview

    J. Lab. Clin. Med.

    (2005)
  • B.C. Blaxall

    Differential gene expression and genomic patient stratification following left ventricular assist device support

    J. Am. Coll. Cardiol.

    (2003)
  • A. Kasai

    Apelin is a novel angiogenic factor in retinal endothelial cells

    Biochem. Biophys. Res. Commun.

    (2004)
  • M. Jaszberenyi

    Behavioral, neuroendocrine and thermoregulatory actions of apelin-13

    Neuroscience

    (2004)
  • Cited by (118)

    • Adipokines in vascular calcification

      2021, Clinica Chimica Acta
    • [MeArg<sup>1</sup>, NLe<sup>10</sup>]-apelin-12: Optimization of solid-phase synthesis and evaluation of biological properties in vitro and in vivo

      2020, Peptides
      Citation Excerpt :

      This work continues our research on synthesis and study of properties of the peptide M. Its goals are (i) the development of an optimized method for Fmoc solid-phase peptide synthesis (SPPS) of peptide M, (ii) a comparative assessment of the proteolytic stability of this peptide and natural apelin-12 in human blood plasma by 1H NMR technique and (iii) the study of the effect of infusion of these peptides on the heart function in rabbits with cardiomyopathy. The last goal of our work was initiated by studies showing the prominent role of the apelin-APJ system in the pathogenesis of heart failure [2,3] and the ability of exogenous apelin-13 to improve LV function in animals and humans with this pathology [20–23]. We used a chemotherapeutic drug doxorubicin (Dox) as a cumulative cardiotoxic agent causing cardiomyopathy [24].

    • Load-dependent effects of apelin on murine cardiomyocytes

      2017, Progress in Biophysics and Molecular Biology
    View all citing articles on Scopus
    View full text