br Apelin Discovered in apelin

Apelin Discovered in 1998, apelin was initially identified as the sole endogenous ligand for the APJ receptor (Tatemoto et al., 1998). Apelin-77 (pre-pro-apelin) is the precursor for various pharmacologically active apelin isoforms (e.g. apelin-12, -13, -17 and 36), and it shares 75–95% sequence homology among various species including rat, mice and human (Lee et al., 2000). N-terminal residues of apelin-77 are post-translationally modified by endopeptidase to form pro-apelin-55, which is further cleaved to apelin-36, -17, -13 and 12. Each of these fragments has a conserved C-terminal region, which is essential for APJ receptor binding and functional activity (Pitkin, Maguire, Bonner, & Davenport, 2010). Post-translational modification of the N-terminal residue of apelin-13 with cyclized glutamine forms [Pyr]-apelin-13, which evades enzymatic degradation and results in a longer biological duration of action (Zhen, Higgs, and Gutierrez, 2013). The different apelin isoforms (i.e. apelin-12, -13, -17 and 36) have variable potency, but apelin-13 and [Pyr]-apelin-13 are identified as the more predominant and potent isoforms in the ana 2 (Maguire, Kleinz, Pitkin, & Davenport, 2009; Tatemoto et al., 1998). More recently, another endogenous APJ receptor-activating peptide, known as Elabela/Toddler (referred to as Elabela) and encoded by the APELA gene, has been discovered (Chng, Ho, Tian, and Reversade, 2013; Pauli et al., 2014). Apelin has potent vascular effects but it is highly prone to proteolytic degradation, thereby limiting its duration of action (Japp et al., 2008). Studies have shown that angiotensin converting enzyme type-2 (ACE-2), a zinc-containing carboxy monopeptidase, is partially responsible for apelin metabolism (Vickers et al., 2002; Wang et al., 2016; Yang, Kuc, et al., 2017). [Pyr]-apelin-13 is more susceptible to ACE-2 degradation than is apelin-17, and results in metabolites, i.e. [Pyr]-apelin-12 and apelin-16, respectively, that have reduced functional activity (Wang et al., 2016). Another recent report showed that ACE-2 metabolizes [Pyr1]-apelin-13 to biologically active [Pyr1]-apelin-13 (1−12), suggesting a beneficial effect of increased ACE-2 expression during cardiovascular diseases (Yang, Kuc, et al., 2017). The metalloprotease, neprilysin, has also been shown to be involved in the degradation of apelin. Neprilysin, by truncating the RPRL (Arg2- Leu5) region of apelin, forms a peptide that is devoid of the ability to activate APJ receptors (McKinnie et al., 2016). The apelin gene is located on band q25–26.1 of chromosome X and is expressed in vascular endothelial cells of both conduit and resistant arteries (Kawamata et al., 2001; Medhurst et al., 2003; Pitkin, Maguire, Kuc, & Davenport, 2010; Pope, Roberts, Lolait, & O'Carroll, 2012). Kleinz et al. reported that the apelin gene is localized to endothelial cells, but not to vascular smooth muscle cells or adipocytes in human saphenous vein, and coronary, pulmonary, and mammary arteries; however, intrarenal arterial endothelial cells lack apelin-like immunoreactivity (Kleinz & Davenport, 2004). It is worth noting that although the apelin peptide is usually absent in vascular smooth muscle cells, it is expressed in smooth muscle cell positive atherosclerotic plaques (Pitkin, Maguire, Kuc, & Davenport, 2010). Moreover, atherosclerotic plaque apelin is co-localized with APJ receptors, suggesting the possibility of apelin-APJ signaling in coronary atherosclerosis. Regulation of apelin gene expression and secretion of apelin from intracellular sources in the blood vessel wall (e.g. adipocytes, endothelial cells) is complex. Numerous factors and conditions increase apelin gene expression, including cytokines (tumor necrosis factor-alpha) (Daviaud et al., 2006), lipopolysaccharides (Han, Wang, Qi, Englander, & Greeley Jr, 2008), hypoxia (Eyries et al., 2008; Glassford et al., 2007), dehydration (Reaux-Le Goazigo, Morinville, Burlet, Llorens-Cortes, and Beaudet, 2004), and insulin (Boucher et al., 2005). In humans, hyperinsulinemia up-regulates apelin gene expression in adipose tissue and increases apelin release via phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC)-dependent pathways (Castan-Laurell et al., 2008). Hypoxia increases apelin gene expression in cultured human pulmonary arterial endothelial and smooth muscle cells via hypoxia inducible factor–1α (HIF-1α) dependent mechanism (Eyries et al., 2008). Activation of α-retinoic acid receptors by all-trans retinoic acid increases apelin gene expression in HUVEC cells and in carotid arteries from balloon-injured rats (Shi, Yuan, Yang, & Zang, 2017). Although these studies provide insight into several key pathways involved in apelin regulation, the association between apelin gene expression and release of apelin into the circulation and/or surrounding tissues remains poorly understood. Moreover, although administration of exogenous apelin has beneficial effects on cardiovascular diseases (Japp et al., 2008; Tatemoto et al., 2001), our knowledge of the role of endogenous apelin, as well as the stimuli for apelin release, in cardiovascular health and disease is limited.