The apelin–APJ system in heart failure: Pathophysiologic relevance and therapeutic potential
Introduction
Heart failure constitutes a major and growing health burden in developed nations. Despite considerable treatment advances over the past two decades, it has a prognosis worse than that of many cancers and results in severe morbidity with impaired quality of life and recurrent hospitalisation [1], [2]. The development of novel treatments for patients with heart failure therefore remains a major priority. G protein-coupled receptors (GPCRs) play an essential role in the physiological control of the cardiovascular system and represent a major target for existing pharmacological treatments [3], [4]. Many of the recent pharmacological advances in the treatment of heart failure, including angiotensin II type 1 (AT1) and beta-adrenergic receptor blockers, have arisen through the specific targeting of GPCR systems, and have provided additive incremental morbidity and mortality benefits [5], [6].
In 1993 a novel GPCR called APJ was identified through the Human Genome Project [7]. Despite sharing significant sequence homology with AT1, APJ did not display specific binding for angiotensin II and remained orphaned until 1998 when its endogenous ligand was identified from bovine stomach extracts and named apelin (APJ endogenous ligand) [8]. Since its discovery, the apelin–APJ system has emerged as an important regulator of cardiovascular homeostasis that may play a role in the pathophysiology of heart failure and represents an exciting target for the development of new therapies [9], [10], [11].
In this article we will review the biology of the apelin–APJ system and its role in cardiovascular homeostasis. We will then discuss the evidence for altered apelin–APJ regulation in the setting of heart failure and consider how attenuated apelin signalling may contribute to the pathophysiology of this condition. Finally we will explore the therapeutic potential of targeting the apelin–APJ system in heart failure and, in particular, the rationale for augmenting apelin–APJ activity as a means of preserving and restoring cardiac performance.
Section snippets
Apelin
The apelin gene, located on the long arm of the human X chromosome, encodes a 77 amino acid preproprotein that is then cleaved to shorter active peptides (Fig. 1) [8], [12], [13]. The full-length mature peptide comprises 36 amino acids (apelin-36) and was originally isolated from bovine stomach extracts. Gel filtration chromatography of bovine colostrum confirmed the presence of apelin-36 and revealed a second peak of activity corresponding to a 13 amino acid peptide (apelin-13), which has
Anatomy: tissue localisation of APJ and apelin
The apelin–APJ system has wide representation in the central nervous system and a variety of peripheral tissues (Fig. 2; for review see ref. [9]). In some tissues, such as lung, kidney and adrenal gland, APJ expression may be restricted to the vasculature, though out with the cardiovascular system, APJ receptors have been detected in neurons of the cerebral cortex, hippocampus and hypothalamus, pituitary gland cells, enterochromaffin-like gastric cells, pancreatic islet cells, osteoblasts and
Animal models of heart failure
Expression of apelin and APJ is increased or maintained in animals with left ventricular hypertrophy and compensated heart failure but downregulated in those with severe, decompensated heart failure. This downregulation may be related to increased activity of the renin–angiotensin–aldosterone system (RAAS). In one heart failure model, several pharmacological treatments retarded the progression to CHF, but only AT1 receptor antagonism prevented the downregulation of apelin–APJ expression.
A novel neurohormonal target in heart failure?
The success of neurohormonal blockade in heart failure [68] has prompted hopes that the pharmacological manipulation of other biological molecules active in disease progression may yield further advances in treatment. A related strategy is to enhance the activity of endogenous mechanisms such as the natriuretic peptide system [69] that oppose the unfavourable haemodynamic changes and pathological cardiac remodelling characteristic of CHF. Nesiritide, an intravenous form of human B-type
Preclinical studies
The cardiovascular effects of acute apelin administration in rodents are now relatively well characterised but the impact of chronic administration requires further attention. One of the most encouraging findings to date with apelin is the enhancement of cardiac performance with chronic administration that occurred without inducing left ventricular hypertrophy. Further studies are required to confirm this finding over longer treatment periods and to establish the effects of chronic dosing in
Conclusion
The cardiovascular profile of the apelin–APJ system makes it an attractive therapeutic prospect for patients with heart failure. Emerging evidence from preclinical models suggests that, as well as improving cardiac performance in established heart failure apelin may preserve myocardial function in the face of chronic cardiac stress and afford protection during acute myocardial injury. Detailed clinical investigation is now required to characterise the in vivo cardiovascular effects of apelin in
Acknowledgement
AGJ is currently supported by a British Heart Foundation Clinical Ph.D. Training Fellowship (FS/06/064).
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2022, Comprehensive PharmacologyIn vitro metabolism of synthetic Elabela/Toddler (ELA-32) peptide in human plasma and kidney homogenates analyzed with mass spectrometry and validation of endogenous peptide quantification in tissues by ELISA
2021, PeptidesCitation Excerpt :A similar discrepancy between in vitro plasma half-life in human and rodents were recently reported for [Pyr1]apelin-13 [23], thereby highlighting potential species differences in the repertoire of proteolytic enzymes. Additionally, the observed plasma half-life of ELA-32 in this study was significantly longer than that observed with apelin peptides, whose plasma half-life ranged from 2−8 min in vitro [4,24,25]. Therefore, of the two apelin receptor ligands, ELA may be the most resistant to proteolytic degradation.