Emerging roles of apelin in biology and medicine

Abstract

The family of apelin peptides is derived from a single gene and activates the 7-transmembrane G-protein-coupled receptor (GPCR) APJ. Apelins have been shown to be involved in the regulation of cardiovascular function and fluid homeostasis and interestingly represent substrates for ACE2, a carboxypeptidase recently described as a novel key enzyme in the renin–angiotensin–aldosterone system (RAS). APJ has further been reported to be a coreceptor for the infection of CD4-positive cells with HIV in the central nervous system (CNS).

Apelin-36 and shorter C-terminal sequences have different potencies and efficacies in regulating these functions. Shorter sequences, especially (Pyr¹)apelin-13, are potent regulators of cardiovascular function, while longer peptides such as apelin-36 are more effective in inhibiting human immunodeficiency virus (HIV) infection by blocking the HIV coreceptor APJ. The pyroglutamate modification characteristic of the short apelin peptide (Pyr¹)apelin-13 indicates paramount biological importance of this peptide.

The aim of this review is to compile conclusive evidence for the involvement of apelin/APJ in the regulation of cardiovascular function and HIV pathology, emphasizing the properties of this receptor system that may make it a successful future drug target.

Introduction

The apelin receptor APJ is one of a group of G-protein-coupled receptors (GPCR, Foord et al., in press) that have recently been paired with their cognate peptide ligands using “reverse pharmacology” (Katugampola & Davenport, 2003), and functional evidence suggests a role for this receptor in the regulation of cardiovascular function (Katugampola et al., 2001), fluid homeostasis (Reaux et al., 2001), and as a coreceptor for human immunodeficiency virus (HIV) infection (Choe et al., 1998).

In 1993, O'Dowd and coworkers identified a gene displaying considerable sequence similarity with the angiotensin receptor (AT-1) gene (O'Dowd et al., 1993). Despite the similarity of this novel receptor, termed APJ, to the AT-1 receptor, angiotensin-II did not activate cells expressing the new GPCR. APJ remained an “orphan” receptor until 1998, when Tatemoto and coworkers discovered a selective ligand for the receptor. In Chinese hamster ovary (CHO) cells transiently expressing APJ, they demonstrated activator potential of bovine stomach homogenates, isolating a 36-amino-acid peptide as the active component. Consecutively, cDNA encoding a 77-amino-acid prepropeptide of the novel ligand, called apelin for APJ endogenous ligand, was identified in human and bovine tissue, and interestingly, peptides comprising C-terminal fragments of varying size of the apelin peptide have been shown to activate the receptor (Fig. 1; Habata et al., 1999, Hosoya et al., 2000, Lee et al., 2000, Kawamata et al., 2001).

Messenger RNA encoding both APJ and apelin, as well as the respective peptides, are abundantly expressed in the central nervous system (CNS) of rats and humans, suggesting an important role for the receptor system in central regulatory pathways (Matsumoto et al., 1996, Edinger et al., 1998, Choe et al., 2000, Hosoya et al., 2000, Puffer et al., 2000, Reaux et al., 2001, Medhurst et al., 2003, Lee et al., 2000, Lee et al., 2004a, Lee et al., 2004b). APJ and apelin are also expressed in peripheral tissues with highest levels present in lung, heart, and mammary gland. (Edinger et al., 1998, Tatemoto et al., 1998, Devic et al., 1999, Habata et al., 1999, Choe et al., 2000, Hosoya et al., 2000, Lee et al., 2000, O'Carroll et al., 2000, Katugampola et al., 2001, Saint-Geniez et al., 2002, Saint-Geniez et al., 2003, Chen et al., 2003a, Chen et al., 2003b, Medhurst et al., 2003, Kleinz & Davenport, 2004).

In agreement with the pattern of distribution, apelin and APJ have been shown to regulate fluid homeostasis (Lee et al., 2000, O'Carroll et al., 2000, Reaux et al., 2001, Reaux et al., 2002), proposed to function as a coreceptor mediating infection of central nervous system cells with human immunodeficiency virus (Choe et al., 1998, Edinger et al., 1998, Hoffman et al., 1998, Cayabyab et al., 2000, Puffer et al., 2000, Zhou et al., 2003), apelin was shown to be secreted into the colostrum and proposed to regulate immune function (Habata et al., 1999). Interestingly, a large number of studies report cardiovascular actions of apelin/APJ. Apelin produces endothelium-dependent vasodilator actions in vivo (Tatemoto et al., 2001), as well as positive inotropic actions in the heart (Szokodi et al., 2002), and more recently, differences in apelin/APJ expression observed in patients with chronic heart failure suggest a role for apelin/APJ in the regulation of cardiovascular function (Chen et al., 2003a, Chen et al., 2003b).

The purpose of this review is to present the evidence for a role of the apelin/APJ receptor system in mammalian physiology and pathophysiology and to discuss possible clinical implications and putative pharmacological strategies.