Review ArticleThe Emerging Potential of the Apelin-APJ System in Heart Failure
Section snippets
Apelin
The peptide apelin is the ligand for the APJ receptor and was first isolated in 1998.4 Its gene is located on the X chromosome, and it is synthesized as a 77–amino acid pre-pro-peptide which is cleaved by as yet unknown peptidases to form mature apelin peptides of varying lengths. All mature peptides conserve the C-terminal portion of the pre-pro-peptide. The 36–amino acid peptide (apelin-36) is the full-length mature peptide, and the 13–amino acid peptide with a post-translational
APJ Receptor
APJ is a 377–amino acid 7–transmembrane domain G-protein–coupled receptor whose gene is localized to the long arm of chromosome 11. Although it bears a striking similarity in both structure and distribution to the angiotensin II type 1 receptor, it shows no affinity for angiotensin II.12 In the healthy human cardiovascular system, the APJ receptor has been identified in cardiomyocytes, endothelial, and vascular smooth muscle cells of the intima and media of epicardial coronary artery, aorta,
Cardiovascular Effects of Apelin Knockout
Apelin-knockout mice display progressive and significant left ventricular (LV) dilation and systolic dysfunction by the age of 6 months. Remarkably, a 2-week subcutaneous apelin infusion leads to full restoration of cardiac dimensions and function,15 confirming that the apelin-APJ system has a significant role in the maintenance of normal cardiac function. Apelin-knockout mice also suffer larger areas of infarction, more extensive LV remodeling, and higher mortality rate than wild-type control
Effects of Exogenous Apelin on the Failing Heart
The inotropic effects of apelin appear to be preserved in experimental HF. In a rat model of ischemic HF, apelin potentiated sarcomere shortening and increased conduction velocity in ventricular myocytes and up-regulated the Na+/H+ exchanger.38 Significant increases in LV stroke volume and contractility in failing hearts have also been observed in various in vivo models.40, 42, 43, 44 Similar effects have also been demonstrated in a rat model of right ventricular failure.45 The ability of
Adipose Tissue Metabolism and Tumor Necrosis Factor α
Since the identification of the synthesis and secretion of numerous cardioactive peptide hormones by adipocytes, adipose tissue has emerged as a mediator of cardiovascular function.81 Over recent years much attention has been focused on the role and interactions of adipose tissue in HF. Initial findings suggest that apelin synthesis is influenced not only by angiotensin II but also by the proinflammatory cytokine tumor necrosis factor (TNF) α, another established pathophysiologic mediator of
Conclusion
Initial studies have outlined a potentially promising profile for therapeutic augmentation of the apelin-APJ system in HF. The recent suggestion that short-term outcomes may be improved in acute decompensated HF by infusion of another endogenous vasodilator, relaxin,94 has raised the possibility of such agents adding incremental benefit to contemporary HF therapy. The majority of disease-modifying HF therapies are aimed at the inhibition and down-regulation of deleterious neurohormonal axes.
Disclosures
None.
References (97)
- et al.
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor
Biochem Biophys Res Commun
(1998) - et al.
Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin
J Biol Chem
(2000) - et al.
Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma
Anal Biochem
(2013) - et al.
Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells
Regul Pept
(2004) - et al.
Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure
Biochem Biophys Res Commun
(2003) - et al.
A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11
Gene
(1993) - et al.
Immunocytochemical localisation of the apelin receptor, APJ, to human cardiomyocytes, vascular smooth muscle and endothelial cells
Regul Pept
(2005) - et al.
Apelin activates L-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas
Peptides
(2007) - et al.
Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids
Regul Pept
(2007) - et al.
Vascular effects of apelin in vivo in man
J Am Coll Cardiol
(2008)
Emerging roles of apelin in biology and medicine
Pharmacol Ther
Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo
J Biol Chem
The novel peptide apelin lowers blood pressure via a nitric oxide dependent mechanism
Regul Pept
Effect of apelin on glomerular hemodynamic function in the rat kidney
Kidney Int
Direct effects of apelin on cardiomyocyte contractility and electrophysiology
Biochem Biophys Res Commun
Effects of acute intravenous infusion of apelin on left ventricular function in dogs with advanced heart failure
J Card Fail
Apelin protects myocardial injury induced by isoproterenol in rats
Regul Pept
Apelin increases contractility in failing cardiac muscle
Eur J Pharmacol
Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase
Regul Pept
Exercise training promotes expression of apelin and APJ of cardiovascular tissues in spontaneously hypertensive rats
Life Sci
Down-regulation of cardiac apelin system in hypertrophied and failing hearts: possible role of the angiotensin II–angiotensin type I receptor system
J Mol Cell Cardiol
Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase
J Biol Chem
Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system
J Am Coll Cardiol
Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes
J Card Fail
Apelin: a new plasma marker of cardiopulmonary disease
Regul Pept
Early and late effects of cardiac resynchronization therapy on force-frequency relation and contractility regulating gene expression in heart failure patients
Heart Rhythm
Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy
Regul Pept
Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure
J Am Coll Cardiol
Effect of sinus rhythm restoration after electrical cardioversion on apelin and brain natriuretic peptide prohormone levels in patients with persistent atrial fibrillation
Am J Cardiol
Myocardial apelin production is reduced in humans with left ventricular systolic dysfunction
J Card Fail
The 212A variant of the APJ receptor gene for the endogenous inotrope apelin is associated with slower heart failure progression in idiopathic dilated cardiomyopathy
J Card Fail
The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives
Trends Cardiovasc Med
Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding
Regul Pept
An obesity paradox in acute heart failure: analysis of body mass index and inhospital mortality for 108,927 patients in the Acute Decompensated Heart Failure National Registry
Am Heart J
Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial
Lancet
Clinical epidemiology of heart failure
Heart
Economics of chronic heart failure
Eur J Heart Fail
Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people
Circulation
[Pyr1]Apelin-13 identified as the predominant apelin isoform in the human heart. vasoactive mechanisms and inotropic action in disease
Hypertension
Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction
Circulation
Apelin, a newly identified adipokine up-regulated by insulin and obesity
Endocrinology
[125I]-(Pyr1) Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man
Br J Pharmacol
Impaired heart contractility in apelin gene–deficient mice associated with aging and pressure overload
Circ Res
Loss of apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic apelin analogues
J Am Heart Assoc
Apelin-13 deteriorates hypertension in rats after damage of the vascular endothelium by ADMA
Can J Physiol Pharmacol
Modulation of the apelin/APJ system in heart failure and atherosclerosis in man
Br J Pharmacol
Interactions between apelin and angiotensin II on rat portal vein
J Renin Angiotensin Aldosterone Syst
Apelin stimulates myosin light chain phosphorylation in vascular smooth muscle cells
Arterioscler Thromb Vasc Biol
Cited by (46)
Role of MicroRNAs and their corresponding ACE2/Apelin signaling pathways in hypertension
2022, Microbial PathogenesisEffects and signaling pathways of Elabela in the cardiovascular system
2022, PeptidesCitation Excerpt :In addition, Elabela enters the maternal circulation and regulates cardiorenal function, exerting direct effects on maternal glomerular endothelial cells [29,30]. The Apelin-APJ System has beneficial effects in cardiovascular diseases such as atherosclerosis, myocardial infarction (MI), heart failure, arrhythmias and pulmonary hypertension [3,31–38]. Elabela as a cognate ligand also plays a role in a variety of diseases.
Recombinant Fc-Elabela fusion protein has extended plasma half-life andmitigates post-infarct heart dysfunction in rats
2019, International Journal of CardiologyCitation Excerpt :Conversely, exogenous administration of apelin mitigates cardiac dysfunction, myocardial infarction (MI) and fibrosis, and protects the heart from ischemia in several models [10–15]. Thus, activation of APJ by apelin has been considered as a new therapeutic approach for HF and other cardiovascular conditions [16–18]. Elabela (ELA) [19] or Toddler [20] is a new peptide hormone acting on APJ to regulate the development of the cardiovascular system at the embryonic stage in zebrafishes and ELA-APJ signaling is conserved and functional in mammalian systems [21], establishing ELA as a new endogenous ligand for APJ.
Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents
2019, European Journal of Medicinal ChemistryCitation Excerpt :Apelins are endogenous peptide hormones and ligands for APJ, a G-protein-coupled receptor. They are crucial in regulating cardiovascular functions, fluid homeostasis and carbohydrate and fat metabolism [6–8]. Apelin is expressed as a 77-amino acid prepropeptide, that is further processed to bioactive C-terminal fragments including apelin-13 (or the N-terminal pyroglutamate pyr-apelin-13), apelin-17 and apelin-36.
See page 495 for disclosure information.