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  • cdna kit br Introduction The apelin receptor angiotensin rec

    2024-11-07


    Introduction The apelin receptor (angiotensin receptor-like 1, APJ) is a seven transmembrane receptor (7TMR) that belongs to the class A peptidergic G protein-coupled receptors (GPCR) superfamily [1]. The endogenous ligands of APJ are the different isoforms of apelin (namely apelin-13, −17, and −36) [2] as well as the recently discovered ELABELA/Toddler [3]. The apelinergic axis is known to be widely distributed throughout the body, both in the central nervous system and at the periphery [[4], [5]]. Peripherally, components of the apelin/APJ system are mainly expressed in the lungs, kidneys, pancreas as well as in the cdna kit [6]. Recently, the apelinergic system has been highlighted as a potential and promising target for drug development [7]. Indeed, modulating APJ signaling can be considered for the treatment of diabetes, obesity, cancer, and HIV infection [4]. However, the most important role of the apelin-APJ axis remains associated to its cardiovascular actions. Indeed, apelin peptides act as potent regulators of vascular function and exert one of the most powerful positive inotropic actions [8]. Accordingly, the apelin-APJ axis is widely distributed within the cardiovascular system, being expressed on endothelial cells, vascular smooth muscle cells and cardiomyocytes [9]. In preclinical models, APJ activation induces a significant drop in mean arterial blood pressure (MABP), reduces ventricular preload and afterload, increases myocardial contractility, and decreases angiotensin II-induced myocardial hypertrophy and fibrosis (for review see [[10], [11]]). In rodents, the hypotensive actions of apelin-13 and apelin-17 are blocked by a pretreatment with L-NAME, a nitric oxide (NO) synthase inhibitor [12]. These beneficial/protective effects of apelin are paralleled in healthy volunteers and in chronic heart failure patients, in whom an intravenous (i.v.) injection of apelin-13 induces a vasodilation of coronary and peripheral blood vessels leading to a lowering of MABP, while increasing the cardiac output [[13], [14]]. In support of the role of the apelin/APJ system in cardiovascular function and pathology, plasma levels of apelin are markedly decreased in patients with chronic heart failure and failing human hearts also exhibit altered apelin and APJ gene expression patterns [[15], [16]]. At the cellular level, activation of APJ triggers several intracellular signaling pathways such as the activation of the Gαi/o pathway leading to inhibition of adenylate cyclase and a lowering of cAMP production [5]. Apelin-13 binding to APJ also induces the phosphorylation of the mitogen-activated protein kinase (MAPK) ERK1/2 by a Gαi/o-dependent mechanism since this effect is blocked by a pretreatment with pertussis toxin (PTX) [17]. APJ activation further induces the recruitment of both β-arrestins 1 and 2 (βarrs), leading to receptor internalization [[18], [19]]. Interestingly, intracellular trafficking routes seem to be agonist-dependent with, on the one hand, apelin-13 and −17, which induce a transient interaction between APJ and βarr, and on the other hand, apelin-36, which displays a long lasting APJ/βarr interaction [20]. Structure-activity relationship (SAR) and alanine-scan have highlighted that the N-terminal amino acids of apelin-13 (i.e. Arg2-Pro3-Arg4-Leu5) are involved in binding to APJ and activation of the Gαi/o signaling pathway [5]. However, the C-terminal of apelin plays a crucial role in modulating APJ internalization and βarr recruitment as well as being responsible for the APJ-dependent hypotensive response [[18], [21]]. Indeed, the truncation of the C-terminal Phe residue or its replacement by Ala in apelin-13 or apelin-17 results in an impairment of the MABP lowering effect of these compounds [22]. Accordingly, we recently published that the substitution of Phe13 by unnatural amino acids induces changes in cAMP production and also affects the hypotensive action of these C-terminal modified apelin-13 analogs [19]. Herein, we examined the APJ signaling profile of a series of C-terminal modified analogs by studying their ability to activate Gαi1, GαoA, inhibit cAMP production, and recruit βarrs. We further monitored the potency of these compounds to elicit changes in MABP in rodents. To pair APJ receptor activity with its physiological effects, we finally applied the Black and Leff operational model to correlate the drop in MABP with a specific signaling signature.