Review Article
The Emerging Potential of the Apelin-APJ System in Heart Failure

https://doi.org/10.1016/j.cardfail.2015.03.007Get rights and content

Highlights

  • The apelin-APJ system is a novel neurohormonal pathway with vasodilator, inotropic, and aquaretic properties as well an apparent antagonistic relationship with the renin-angiotensin system.

  • It is down-regulated in HF, and there is a growing interest around the therapeutic potential of up-regulating this system in acute and chronic HF.

  • Early data suggest that apelin infusion is safe in HF and that its vasodilator action is maintained.

  • Further work is required to ascertain the effects of potentiation of the apelin-APJ system in acute and chronic HF.

Abstract

The apelin-APJ system is a novel neurohormonal pathway, with studies to date suggesting that it may be of pathophysiologic relevance in heart failure and may indeed be a viable therapeutic target in this syndrome. This interest is driven primarily by the demonstration of its vasodilator, inotropic, and aquaretic actions as well as its apparent antagonistic relationship with the renin-angiotensin system. However, its promise is heightened further by the observation that, unlike other and more established cardioprotective pathways, it appears to be down-regulated in heart failure, suggesting that augmentation of this axis may have a powerful effect on the heart failure syndrome. We review the literature regarding the apelin-APJ system in heart failure and suggest areas requiring further research.

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.

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