Cardiovascular effects of a PEGylated apelin

Jia, Zhiyong; Hou, Lihui; Léger, A.; Wu, I-Hsien; Kudej, Amelia B.; Stefano, James E.; Jiang, Caihui; Pan, Chun-Ming; Akita, Geoffrey Y.

doi:10.1016/j.peptides.2012.09.003

Cited by 45 publications

(35 citation statements)

References 22 publications

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“…appended to the N terminus of apelin-36, has been shown to exhibit enhanced cardiovascular activity and extended half-life as compared with unmodified apelin-36 (17). However, we have found that attaching PEG molecules at either the N terminus or the C terminus of apelin-36 disrupted the metabolic activity of the peptide (discussed further below and see Fig.…”

Section: Table 1 Properties Of Apelin Peptides and Variantsmentioning

confidence: 78%

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: Table 1 Properties Of Apelin Peptides and Variantsmentioning

confidence: 78%

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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“…The first reported study to attempt this approach with apelin peptides was by Jia and colleagues. 58,60 The authors utilized PEG branched aldehydes of 10, 30, and 40 kDa to conjugate apelin-36 and found that the larger molecular weight PEG conjugation occurred primarily once and on the N-terminal nitrogen. The 10 kDa PEG coupling was less specific, and levels of mono-PEGylated apelin-36 were <20%.…”

Section: Pursuit Of Metabolically Stable Apelin Analogsmentioning

confidence: 99%

Regulation of the Apelinergic System and Its Potential in Cardiovascular Disease: Peptides and Small Molecules as Tools for Discovery

et al. 2015

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Apelin peptides and the apelin receptor represent a relatively new therapeutic axis for the potential treatment of cardiovascular disease. Several reports suggest apelin receptor activation with apelin peptides results in cardioprotection as noted through positive ionotropy, angiogenesis, reduction of mean arterial blood pressure, and apoptosis. Considering the potential therapeutic benefit attainable through modulation of the apelinergic system, research is expanding to develop novel therapies that limit the inherent rapid degradation of endogenous apelin peptides and produce metabolically stable small molecule agonists and antagonists to more rigorously interrogate the apelin receptor system. This review details the structure–activity relationships for chemically modified apelin peptides and recent disclosures of small molecule agonists and antagonists and summarizes the peer reviewed and patented literature. Development of metabolically stable ligands of apelin receptor and their effects in various models over the coming years will hopefully lead to establishment of this receptor as a validated target for cardiovascular indications.

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“…These assumptions were made after observing the effects of experimental iv administration of apelin to animals and humans with heart failure: it acts as a potent inotrope and increases the contractility of the heart, the ejection fraction and the cardiac output and lowers the left ventricle diastolic pressure . These effects were described initially on isolated hearts on which apelin exerted a clear inotropic effect, especially on failing myocardium [23,24], and then were reproduced on healthy and heart failure human volunteers [25,26]. All these scientific results are proof of the beneficial role of apelin in the human body and in particular in the functioning of the cardiovascular system but it suggests its limited protective effect until it is overcome by the injurious molecular pathway and its tissular and serum level begin to fall.…”

Section: Introductionmentioning

confidence: 98%

Serum level of apelin-13 negatively correlated with NT-proBNP in heart failure patients

Goidescu

Anton

Leucuţa

et al. 2016

Revista Romana De Medicina De Laborator

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Background: Apelin is a potent endogenous inotropic peptide with a major role in counteracting the aldosterone and angiotensin II and their negative effects on the cardiovascular system. The exact role of apelin in the pathophysiology of this disease is not well understood. We aimed to investigate the possible associations of apelin-13with clinical and paraclinical characteristics in HF patients as well as studying its dynamics during the course of the heart failure. Method: We performed a prospective observational cohort single-center study. We compared the baseline serum levels of apelin-13 and NT-proBNP level in 53 heart failure patients (acute heart failure, chronic compensated heart failure and chronic decompensated heart failure). We divided the patients according to the apelin-13 level: above and below the median, and we analyzed the relationship between serum apelin-13 and the clinical, echocardiographic, electrocardiographic and biological parameters. Twenty patients were followed-up (after an average time interval of 9 months), investigating the same parameters. Results: The median of apelin-13 was 495pg/mL . We found strong, negative correlation between the serum levels of apelin-13 and p<0.001). For the reassessed patients the median apelin level was significantly higher at follow-up (460 pg/mL, IQR 342-871 pg/mL) as compared with the baseline level (395 pg/mL, IQR 270-603 pg/mL), p=0.019, and maintained the negative correlation with p<0.001

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Cardiovascular effects of a PEGylated apelin

Cited by 45 publications

References 22 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

Regulation of the Apelinergic System and Its Potential in Cardiovascular Disease: Peptides and Small Molecules as Tools for Discovery

Serum level of apelin-13 negatively correlated with NT-proBNP in heart failure patients

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