Hepatic and cardiac beneficial effects of a long‐acting Fc‐apelin fusion protein in diet‐induced obese mice

Wang, Weimin; Zhang, Dongming; Yang, Rongze; Xia, Weiya; Qian, Kun; Shi, Zhengrong; Brown, Robert A.; Zhou, Huifen; Xi, Yue; Shi, Lin; Chen, Ling; Xu, Feng; Sun, Xiaojian; Zhu, Dalong; Gong, Da-Wei

doi:10.1002/dmrr.2997

Cited by 18 publications

(17 citation statements)

References 52 publications

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“…In the present study, we show a protective role of the long-acting Fc-apelin fusion protein 22 against LPS-induced liver injury. The administration of LPS induced serum ALT elevation, indicating a liver damage.…”

Section: Discussionsupporting

confidence: 68%

“…The production of Fc-apelin fusion protein is described previously 22 . In brief, the human IgG Fc-region is conjugated with apelin-13 at the N-terminus through the 3x linker of [Gly-Gly-Gly-Gly-Ser (GGGGS)] 23 .…”

Section: Methodsmentioning

confidence: 99%

“…Yet, apelin is a small peptide and has a very short in vivo half-life of about 8 mins 19 , 20 , which wound limit its clinical application 21 . To prolong its half-life, we engineered an apelin fusion protein by conjugating the Fc-fragment of human IgG with the apelin-13 peptide, resulting in Fc-apelin-13 (abbreviated as Fc-apelin hereafter) 22 . The fusion protein has an extended in vivo half-life of about 33 hours and has shown beneficial effects of improving insulin sensitivity and cardiac output in obese mice.…”

Section: Introductionmentioning

confidence: 99%

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Fc-apelin fusion protein attenuates lipopolysaccharide-induced liver injury in mice

Zhou

Yang

Wang

et al. 2018

Sci Rep

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Apelin is a peptide hormone with anti-oxidative and anti-inflammatory activities and is proposed to be a potential therapeutic for many disease conditions, including sepsis. However, short in vivo half-life of the apelin peptide would limit its potential clinical applications. This study aims to investigate the effects of Fc-apelin, a novel long-acting apelin fusion protein, on lipopolysaccharide (LPS)-induced liver injury. Liver injury was induced by systemic injection of LPS in mice. Hepatoprotective activities of Fc-apelin against inflammation were evaluated in LPS mice and/or hepatoma Huh-7 cells with respect to serum ALT, apoptosis, oxidative stress, macrophage infiltration and gene expression. We found that LPS induced systemic inflammation and liver damage. Co-administration of Fc-apelin significantly attenuated serum ALT elevation, diminished LPS-induced apoptosis and ROS production in the liver and in Huh-7 cells, mitigated hepatic macrophage infiltration, and reduced TNFα and IL-6 gene expression. Collectively, Fc-apelin fusion protein exerts protective effects against LPS-induced liver damage and may serve as a potential therapeutic for endotoxin-induced liver injury.

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Section: Discussionsupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fc-apelin fusion protein attenuates lipopolysaccharide-induced liver injury in mice

Zhou

Yang

Wang

et al. 2018

Sci Rep

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“…The apelin system displays major physiological roles in vascular and lymphatic development [155,156], in neurology [157], and in the digestive system [158]. The activation of the apelin system has demonstrated many beneficial effects in cardiovascular, kidney, skin, and metabolic diseases [128,142,150,159,160,161,162,163,164]. Apelin has aroused a special interest in the field of cardiology since it is one of the most powerful dose-dependent positive inotropic agents known to date, as demonstrated in perfused hearts [153].…”

Section: The Apelin System In Health and Diseasementioning

confidence: 99%

Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis

Melgar-Lesmes

Perramón

Jiménez

2019

Cells

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Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology—both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.

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“…N‐PEGylation and N‐palmitoylation of the native peptides also increased plasma stability by several orders of magnitude while maintaining good Ca 2+ mobilization . Interestingly, preserved agonist activity with prolonged in vivo half‐life was also achieved by fusing apelin‐13 to IgG Fc fragment or by encapsulating Pyr 1 ‐apelin‐13 in PEGylated liposomal nanocarriers . More recently, the addition of a fluoroalkyl chain to the N‐terminal part of apelin‐17 was shown to strongly increase plasma stability while maintaining its in vitro pharmacological properties and significantly improving the in vivo activity of the peptide on diuresis and arterial blood pressure …”

Section: Toward Pharmacological Probes and Novel Drugsmentioning

confidence: 99%

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

Marsault

Llorens-Cortes

Iturrioz

et al. 2019

Annals of the New York Academy of Sciences

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The apelinergic pathway has been generating increasing interest in the past few years for its potential as a therapeutic target in several conditions associated with the cardiovascular and metabolic systems. Indeed, preclinical and, more recently, clinical evidence both point to this G protein-coupled receptor as a target of interest in the treatment of not only cardiovascular disorders such as heart failure, pulmonary arterial hypertension, atherosclerosis, or septic shock, but also of additional conditions such as water retention/hyponatremic disorders, type 2 diabetes, and preeclampsia. While it is a peculiar system with its two classes of endogenous ligand, the apelins and Elabela, its intricacies are a matter of continuing investigation to finely pinpoint its potential and how it enables crosstalk between the vasculature and organ systems of interest. In this perspective article, we first review the current knowledge on the role of the apelinergic pathway in the above systems, as well as the associated therapeutic indications and existing pharmacological tools. We also offer a perspective on the challenges and potential ahead to advance the apelinergic system as a target for therapeutic intervention in several key areas.

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Hepatic and cardiac beneficial effects of a long‐acting Fc‐apelin fusion protein in diet‐induced obese mice

Cited by 18 publications

References 52 publications

Fc-apelin fusion protein attenuates lipopolysaccharide-induced liver injury in mice

Fc-apelin fusion protein attenuates lipopolysaccharide-induced liver injury in mice

Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

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