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  • Patients with cardiovascular disorders typically have lower

    2023-01-28

    Patients with cardiovascular disorders typically have lower plasma apelin levels than matched healthy controls. For example, plasma apelin levels are reduced in patients with coronary artery disease (CAD), and among CAD patients with unstable angina or acute myocardial infraction there is a further reduction in apelin levels as compared with asymptomatic CAD patients (Kadoglou et al., 2010). Similarly, plasma apelin levels are reduced in patients with stable angina, essential hypertension and acute coronary syndrome (Li et al., 2008; Gupta et al., 2016). In patients with heart failure, apelin levels vary depending on the stage and severity of the disease, as plasma apelin levels are elevated in early stage heart failure, but significantly reduced in patients with severe disease as compared to healthy controls (Chen et al., 2003). Moreover, the concentration of apelin in myocardial tissue is reduced in patients with heart failure (Chandrasekaran et al., 2010). In contrast to cardiovascular diseases, apelin levels are elevated during metabolic disorders. During obesity, plasma apelin levels are significantly higher than those observed in subjects with normal weight (Boucher et al., 2005), and are further increased in patients with morbid obesity (Heinonen et al., 2005). Similarly, plasma apelin levels are increased in patients with diabetes (Castan-Laurell et al., 2011; Habchi et al., 2014). It is not yet known whether these changes in apelin levels during cardiovascular and metabolic disorders are associated with protective or compensatory roles of the apelinergic system. For example, in some human and animal studies administration of apelin is shown to restore decreased cardiac function, consistent with a beneficial therapeutic effect of apelin (Koguchi et al., 2012; Nagano, Ishida, Unno, Matsukura, & Fukamizu, 2013). In 2013, a second endogenous ligand for APJ receptors was discovered. Elabela has a 32 amino ARRY-380 sequence but does not share sequence homology with apelin (Chng, Ho, Tian, & Reversade, 2013; Pauli et al., 2014); however, the affinity of the peptide for APJ receptors is similar to that of apelin (O'Carroll et al., 2017; Perjes et al., 2016). Nonetheless, evidence suggests that the peptides may not bind in the same way to the orthostatic binding site. Structure-activity relationship studies reveal that the C-terminal moiety (Arg28, Val29, Pro30, Phe31, and Pro32) and His26 residues of Elabela are most important for receptor binding and signaling (Murza et al., 2016). This contrasts markedly with apelin-13, in which the key pharmacophores (Arg2, Pro3, Arg4, Leu5) are primarily located at the N-terminal. Elabela was initially identified as an embryonic APJ receptor regulator, but recent studies suggest its role in adult tissues as well (Perjes et al., 2016; Yang, Read, et al., 2017). Similar to apelin, Elabela is also expressed in vascular endothelial cells (O'Carroll et al., 2017; Perjes et al., 2016). An understanding of the functional role of Elabela in the vascular system is still emerging but recent evidence suggests that Elabela can compensate for down-regulated functions of apelin during various cardiovascular diseases. Administration of exogenous Elabela improves right ventricular systolic pressure and hypertrophy, as well as pulmonary vascular remodeling, in a rat model of pulmonary hypertension in which apelin signaling is downregulated (Yang, Read, et al., 2017). Infusion of Elabela, which was associated with an increase in cardiac output and reduced systemic vascular resistance, improves cardiovascular function and survival in a cecal ligation puncture model of sepsis (Coquerel et al., 2017). On the other hand, reduced levels of Elabela may lead to cardiovascular abnormalities, inasmuch as pregnant Elabela knockout mice display preeclampsia-like symptoms and defective placental angiogenesis (Ho et al., 2017).
    APJ receptor The APJ receptor is a G-protein coupled receptor located on chromosome 11 and composed of an intron-less gene (APLNR), which is conserved in many species including human, monkey, chimpanzee, mouse and rat (Pitkin, Maguire, Bonner, & Davenport, 2010). APJ receptors were first discovered in 1993 during a search for vasopressin receptors (O'Dowd et al., 1993). Immunocytochemical and autoradiographic studies have detected APJ receptors in endothelial and smooth muscle cells in numerous blood vessels, including human coronary, internal mammary, radial, and pulmonary arteries, human saphenous vein, and rat aorta, coronary, cerebral and pulmonary arteries (Katugampola, Maguire, Matthewson, & Davenport, 2001; Kleinz, Skepper, & Davenport, 2005; Mughal, Sun, & O'Rourke, 2018; Pitkin, Maguire, Kuc, & Davenport, 2010).