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  • APJ receptor expression is altered

    2023-09-28

    APJ receptor expression is altered in various cardiovascular diseases, and both increases as well as decreases in APJ receptor expression have been reported. A decrease in mRNA and protein levels of APJ receptors was observed in patients with ischemic heart disease or idiopathic dilated cardiomyopathy (Földes et al., 2003; Pitkin, Maguire, Kuc, & Davenport, 2010); however, APJ receptor protein levels were significantly increased in ischemic heart failure (Atluri et al., 2007; Sheikh et al., 2008). Hypoxia, one of the major consequences of ischemic injury, may lead to increased APJ receptor expression, as hypoxia-activated HIF-1α has been shown to cause aberrant increases in APJ receptor protein expression (Kerkela et al., 2013; Kong et al., 2015; Zhang et al., 2015). APJ receptor mRNA levels are up-regulated in patients with aortic valve stenosis in comparison to controls (Peltonen et al., 2009). Both mRNA and protein levels of APJ receptors are reduced in the heart, kidney and direct thrombin inhibitor of hypertensive rats (Najafipour et al., 2015; Najafipour, Soltani Hekmat, Nekooian, & Esmaeili-Mahani, 2012), whereas in obese women, there is an increase in APJ receptor mRNA levels, which was attenuated by improving insulin resistance (Castan-Laurell et al., 2008).
    Vascular effects of apelin Apelin has complex vasomotor effects as it can cause either vasodilation or vasoconstriction depending on the vascular bed and underlying conditions. These dual actions of apelin are attributed to the presence of APJ receptors in both the endothelial and smooth muscle cell layers of the blood vessel wall. Vasoactive agents may act directly on vascular smooth muscle cells to cause contraction or relaxation, or on endothelial cells, which can secrete substances that mediate vasodilation (e.g. NO, prostacyclin) as well as vasoconstriction (e. g. endothelin) (O'Rourke, Vanhoutte, & Miller, 2006).
    Apelin mimetics and inhibitors
    Conclusions and future directions
    Conflict of interest statement
    Funding source Research in the authors' laboratory is supported by a grant to STO from the National Institutes of Health, National Heart, Lung, and Blood Institute (Grant HL124338).
    Introduction Apelin is a bioactive peptide that was originally identified in bovine stomach extracts as the endogenous ligand of the orphan G protein-coupled receptor APJ [1]. It is derived from a 77-amino-acid prepropeptide that is cleaved into a 55-amino-acid fragment and then into shorter forms. The physiologically active form is thought to be apelin-36, although the pyroglutamylated form of apelin-13, which is also produced endogenously, is more potent. Boucher et al. [2] found that apelin is produced and secreted by mature human and murine adipocytes, and that the apelin mRNA levels found in these cells are similar to those found in the stroma-vascular fraction (which contains other cell types present in adipose tissue) and in organs such as the kidney and heart [2]. In obese humans, plasma apelin levels are significantly higher than in lean controls [2]. Apelin is involved in a broad range of physiological functions, e.g., fluid homeostasis [3], regulation of food intake [4], energy metabolism [5], the cardiovascular system [6] and angiogenesis [7]. Recent data has suggested that apelin, like other adipokines such as resistin [8], [9], adiponectin [10], chemerin [11] and visfatin [12], may affect male and female fertility. Indeed, mRNA and protein expression of apelin and APJ has been reported in several reproductive tissues including the hypothalamus [13], [14], [15], pituitary [14], [15], [16], testis, uterus [17] and ovary [18], [19], [20], [21]. Intracerebroventricular injection of apelin-13 significantly suppressed luteinizing hormone (LH) [22] and follicle-stimulating hormone (FSH) [23] in male rats, and led to decreases in serum testosterone (T) levels [22], [23]. However, the role of apelin in ovarian steroid secretion has only been partly investigated. Recently published data by Roche et al. [24] showed that apelin stimulated progesterone (P4) secretion in cultured human luteinized granulosa cells. The expression of apelin and APJ has been demonstrated in bovine ovarian follicles and corpus luteum (CL) [19], [20], [21], as well as in human ovarian follicles [24]. In ovarian follicles, P4 increases expression of APJ in cultured bovine granulosa cells, while LH induces the expression of apelin and APJ in cultured theca cells, suggesting that apelin has a role in ovarian follicle physiology, e.g., follicle selection and dominance [20]. Published literature led us to hypothesize that apelin is expressed in the porcine ovary and modulates ovarian function by directly affecting cell steroidogenesis and proliferation. Pigs are becoming a valid alternative to traditional non-rodent species in pharmacological, physiological and toxicological studies because many of their physiological characteristics resemble those of humans.