Endogenous regulation of cardiovascular function by apelin-APJ

Charo, David; Ho, Michael; Fajardo, Giovanni; Kawana, Masataka; Kundu, Ramendra K.; Sheikh, Ahmad Y.; Finsterbach, Thomas; Leeper, Nicholas J.; Ernst, K; Chen, Mary M; Ho, Yen-Dong; Chun, Hyung J.; Bernstein, Daniel; Ashley, Euan A.; Quertermous, Thomas

doi:10.1152/ajpheart.00686.2009

Cited by 174 publications

(189 citation statements)

References 36 publications

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“…Further evidence of ligand/receptor promiscuity in the apelin/APJ system is provided by mouse knock-out studies. APJ knock-out mice display a distinct phenotype as compared with apelin knock-out mice with respect to cardiac development and the sensitivity of cardiomyocytes to hypertrophy (26). APJ knock-out mice exhibit embryonic lethality due to defects in heart development, whereas apelin knock-out mice do not (26,27).…”

Section: Discussionmentioning

confidence: 98%

Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

Galon-Tilleman

Yang

Bednarek³

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinApelin-36 was discovered as the endogenous ligand for the previously orphan receptor APJ. Apelin-36 has been linked to two major types of biological activities: cardiovascular (stimulation of cardiac contractility and suppression of blood pressure) and metabolic (improving glucose homeostasis and lowering body weight). It has been assumed that both of these activities are modulated through APJ. Here, we demonstrate that the metabolic activity of apelin-36 can be separated from canonical APJ activation. We developed a series of apelin-36 variants in which evolutionarily conserved residues were mutated, and evaluated their ability to modulate glucose homeostasis and body weight in chronic mouse models. We found that apelin-36(L28A) retains full metabolic activity, but is 100-fold impaired in its ability to activate APJ. In contrast to its full metabolic activity, apelin-36(L28A) lost the ability to suppress blood pressure in spontaneously hypertensive rats (SHR). We took advantage of these findings to develop a longer-acting variant of apelin-36 that could modulate glucose homeostasis without impacting blood pressure (or activating APJ). Apelin-36-[L28C(30kDa-PEG)] is 10,000-fold less potent than apelin-36 at activating the APJ receptor but retains its ability to significantly lower blood glucose and improve glucose tolerance in diet-induced obese mice. Apelin-36-[L28C(30kDa-PEG)] provides a starting point for the development of diabetes therapeutics that are devoid of the blood pressure effects associated with canonical APJ activation.The apelin gene encodes a pre-pro-protein that is processed into a number of regulatory hormones. The best characterized of these peptide hormones are apelin-13, apelin-17, and apelin-36 (1). The 13 C-terminal amino acids of these peptides (comprising apelin-13) are shared, with apelin-17 extending an additional 4 amino acids from the N terminus, and apelin-36 extending a further 19 amino acids beyond the N terminus of apelin-17 (see Table 1). Apelin was discovered as an endogenous agonist of the G protein-coupled receptor APJ (2). Specifically, apelin-36 was purified from bovine stomach tissue extract based on its ability to stimulate signaling through APJ.Through a combination of pharmacological and genetic approaches, apelin has been linked to two major types of biological activities: cardiovascular (stimulation of cardiac contractility and suppression of blood pressure) and metabolic (improving glucose homeostasis and lowering body weight) (3, 4). Both of these activities have been assumed to be mediated solely through APJ, but there is substantial evidence to suggest that APJ may have apelin-independent activities (5, 6). Here, we provide evidence that this ligand-receptor promiscuity goes in both directions, and that apelin may have APJ-independent activities as well. Specifically, we demonstrate that the metabolic activity of apelin-36 can be dissociated from canonical APJ signaling. ResultsTo evaluate the chronic metabolic activity of apelin peptid...

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Section: Discussionmentioning

confidence: 98%

Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

Galon-Tilleman

Yang

Bednarek³

et al. 2017

Journal of Biological Chemistry

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“…In mice, administration of apelin increases myocardial contraction while reducing cardiac preload and afterload, without causing hypertrophy (Ashley et al 2005). Furthermore, apelin increases the shortening of sarcomeres in cardiomyocytes (Farkasfalvi et al 2007), an effect that is impaired in isolated ventricular myocytes from apelin and APJ KO mice (Charo et al 2009). Apelin KO mice have an impaired response to cardiac pressure overload, thus suggesting a role for apelin/APJ in the sustainability and amplification of the cardiac response to stress (Kuba et al 2007).…”

Section: Cardiovascular Roles Of Apelin/apjmentioning

confidence: 99%

“…Cardiovascular development defects have been reported in APJ KO mice, where a loss of homozygous mutants has been described (Charo et al 2009, Kang et al 2013, but not in apelin KO mice (Charo et al 2009), indicating possible ligand-independent effects of the receptor. This effect may perhaps be explained by the recent report that APJ signals independently of apelin in response to cardiac mechanical stretch (Scimia et al 2012).…”

Section: Cardiovascular Roles Of Apelin/apjmentioning

confidence: 99%

“…Apelin/APJ may also have a direct effect on vascular smooth muscle, including vasoconstriction, which may affect renal glomerular hemodynamic function in the rat kidney (Hus-Citharel et al 2008). Some studies have also proposed an immunological role for apelin as it reduces the production of cytokines in mouse spleen cells (Habata et al 1999, Horiuchi et al 2003, Leeper et al 2009), suggesting that apelin may modulate neonatal immune responses through rodent and bovine colostrum and milk. APJ is also a co-receptor of HIV entry into target cells , Edinger et al 1998, Zhang et al 1998, an action that is blocked by apelin (Zou et al 2000).…”

Section: Other Functions Of the Apelinergic Systemmentioning

confidence: 99%

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The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

282

216

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The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

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“…The availability of mice lacking either the ligand or the receptor helps to study the effects of alterations of the endogenous apelin-APJ signaling system. While apelin-deficient mice are viable, fertile and show normal development, APJ-deficient mice display cardiovascular development defects, suggesting the possibility of undiscovered APJ ligands or ligand-independent effects of APJ [18]. An example of such APJ ligand is the ELABELA hormone, which is involved in heart development [19,20] while a ligand-independent effect might consist in the initiation of cardiac hypertrophy in response to stretch [21].…”

Section: The Apj Receptormentioning

confidence: 99%

Effects of apelin on the cardiovascular system

et al. 2015

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Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterised by different numbers of aminoacids. The number of aminoacids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin, can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes of apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long lasting (6 hours) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling. KeywordsApelin/APJ system, heart failure, ischemia-reperfusion injury, contractility, cardiac protection, Reninangiotensin system 2 The apelin/APJ system Apelin In 1998 Tatemoto et al. discovered the endogenous peptide capable of binding the G protein-coupled receptor (GPCR) APJ [1,2], which at that time was considered an orphan receptor becaue its ligand was unknown. The just discovered ligand was called, apelin e.g APj Endogenous LIgaNd. Apelin is expressed in hearts, lungs, kidneys, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma. The gene of apelin is located on chromosome X [3] and encodes a 77 aminoacid sequence called pre-pro-apelin [4]. Upon cleavage by a family of endopeptidases, pre-pro-apelin generates several C-terminal fragments of various size, which are classified on the basis of the number of aminoacids. The active isoforms range from 36 to 12 aminoacids. As fragments shorter than 12 aminoacids are biologically inactive, it appears evident that the Cterminal 12 aminoacids are essential for receptor binding, whereas the N-terminal sequence modulates the interaction with the receptor [5]. At present it is recognized that, although different isoforms display similar functions, active isoforms differ in tissue distribution, potency and receptor binding affinity [6]. Apelin-13 and, to a lesser extent, apelin-36 have been considered the most active isoforms with the greatest activity on the cardi...

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Endogenous regulation of cardiovascular function by apelin-APJ

Cited by 174 publications

References 36 publications

Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

Effects of apelin on the cardiovascular system

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