A network map of apelin-mediated signaling

Dagamajalu, Shobha; Rex, Devasahayam Arokia Balaya; Philem, Pushparani Devi; Rainey, Jan K.; Prasad, T. S. Keshava

doi:10.1007/s12079-021-00614-6

Cited by 9 publications

(6 citation statements)

References 62 publications

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“…Our study, for the first time, demonstrates that n-3 PUFAs protect the heart from IR injury by regulating the PI3K-AKT-mTOR signaling pathway through APLNR inhibition. Activation of the apelin/APLNR system has been shown to regulate the PI3K-AKT-mTOR signaling pathway ( Dagamajalu et al, 2022 ). The PI3K-AKT-mTOR signaling pathway can be activated by GPCR and receptor tyrosine kinase (RTK).…”

Section: Discussionmentioning

confidence: 99%

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids

Zheng,

Tan,

et al. 2023

Front. Pharmacol.

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Background: While the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on cardiac ischemia-reperfusion (IR) injury have been previously reported, limited data are available regarding how these fatty acids affect membrane receptors and their downstream signaling following IR injury. We aimed to identify potential receptors activated by n-3 PUFAs in IR hearts to understand the regulatory mechanisms of these receptors.Methods: We used fat-1 mice, which naturally have elevated levels of n-3 PUFAs, and C57BL/6J mice as a control group to create a myocardial IR injury model through Langendorff perfusion. We assessed the impact of endogenous n-3 PUFAs on left ventricular function, myocardial infarct size, myocardial apoptosis, and ATP production. RNA sequencing (RNA-seq) and bioinformatics analysis were conducted to identify molecular targets affected by n-3 PUFAs. Based on these analyses we then treated IR hearts of WT and fat-1 mice with an antagonist (ML221) or an agonist (apelin-13) for the predicted receptor to assess cardiac contractile function and intracellular signaling pathways. An in vitro hypoxia-reoxygenation (HR) model was also used to confirm the effects of n-3 PUFAs on the examined intracellular signaling pathways.Results: Endogenous n-3 PUFAs protected cardiac structure and function in post-IR hearts, and modulated phosphorylation patterns in the PI3K-AKT-mTOR signaling pathways. RNA-seq analysis revealed that n-3 PUFAs affected multiple biological processes as well as levels of the apelin receptor (APLNR). Consistent with a role for the PLNNR, ML221 synchronized the activation of the PI3K-AKT-mTOR signaling axis, suppressed the expression of PKCδ and phosphorylated p38α, upregulated PKCε expression, upregulated or restored the phosphorylation of myofilaments, and prevented myocardial injury and contractile dysfunction in WT IR hearts. By contrast, apelin-13 disrupted the PI3K-AKT-mTOR signaling axis in post-IR fat-1 hearts. The phosphorylation signaling targeted by APLNR inhibition in post-IR fat-1 hearts was also observed after treating HR cells with eicosatetraenoic acid (EPA).Conclusion: Endogenous n-3 PUFAs protect against post-IR injury and preserve cardiac contractile function possibly through APLNR inhibition. This inhibition synchronizes the PI3K-AKT-mTOR axis, suppresses detrimental phosphorylation signaling, and restores or increases myofilament phosphorylation in post-IR hearts. The beneficial effects observed in fat-1 transgenic mouse hearts can be attributed, at least in part, to elevated EPA levels. This study is the first to demonstrate that n-3 PUFAs protect hearts against IR injury through APLNR inhibition.

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Section: Discussionmentioning

confidence: 99%

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids

Zheng,

Tan,

et al. 2023

Front. Pharmacol.

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“…Additional information, including cell lines used in the experiment, experiment type, and sites and residues of PTMs were also curated. A special attention was given to separate Elabela signaling from that of Apelin‐mediated signaling, because both ligands are known to elicit their reactions through a common receptor‐ APLNR (Dagamajalu et al 2021c). Each molecular event described in the Elabela signaling pathway is hyperlinked to the PubMed entry of the corresponding articles.…”

Section: Methodsmentioning

confidence: 99%

“…Elabela signals through the apelin receptor to mediate downstream signaling cascades. The apelin receptor (APLNR, also known as APJ) is a class A (rhodopsin‐like) G protein‐coupled receptor (GPCR), first identified in 1993 (O'Dowd et al 1993; Dagamajalu et al 2021c). The APLNR gene is located on chromosome 11q12 and encodes a protein of 380 amino acid residues (O'Dowd et al 1993).…”

Section: Introductionmentioning

confidence: 99%

“…This receptor is highly expressed in gastrulation and associated with the development of heart, cardiovascular homeostasis, and cardiac contractility (Chng et al 2013; Perjes et al 2016; Li et al 2017). There are two endogenous peptide ligands for APLNR, namely apelin (Dagamajalu et al 2021c) and Elabela (Li et al 2017). In this study, we developed a signaling pathway map induced by Elabela.…”

Section: Introductionmentioning

confidence: 99%

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The network map of Elabela signaling pathway in physiological and pathological conditions

Dagamajalu

Rex

Suchitha

et al. 2021

J. Cell Commun. Signal.

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Elabela (ELA; also called Apela and Toddler) is one of the recently discovered ligand among the two endogenous peptide ligands (Apelin and Elabela) of the apelin receptor (APLNR, also known as APJ). Elabela-induced signaling plays a crucial role in diverse biological processes, including formation of the embryonic cardiovascular system and early placental development by reducing the chances of occurrence of preeclampsia during pregnancy. It also plays the major role in the renoprotection by reducing kidney injury and the inflammatory response and regulation of gene expression associated with heart failure and fibrosis. Elabela may be processed into different active peptides, each of which binds to APLNR and predominantly activates the signals through PI3K/AKT pathway. Owing to its biomedical importance, we developed a consolidated signaling map of Elabela, in accordance with the NetPath criteria. The presented Elabela signaling map comprises 12 activation/ inhibition events, 15 catalysis events, 1 molecular association, 34 gene regulation events and 32 protein expression events. The Elabela signaling pathway map is freely made available through the WikiPathways Database (https:// www. wikip athwa ys. org/ index. php/ Pathw ay: WP5100).

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“…In this study, we compiled the research articles containing molecular information about urotensin‐II mediated signaling mechanisms and built a detailed pathway map of urotensin‐II mediated UTR signaling. We developed a resource of signaling events mediated by UTR similar to the previously published pathways related to cardiac vascular diseases, including endothelin, apelin and elabela (Dagamajalu et al 2021, 2022a, b). The urotensin‐II mediated UTR signaling pathway described in this study comprises 129 proteins undergoing six different molecular reactions stimulated by urotensin‐II.…”

Section: Introductionmentioning

confidence: 99%

The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions

Rex

Suchitha

Palollathil

et al. 2022

J. Cell Commun. Signal.

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Urotensin‐II is a polypeptide ligand with neurohormone‐like activity. It mediates downstream signaling pathways through G‐protein‐coupled receptor 14 (GPR14) also known as urotensin receptor (UTR). Urotensin‐II is the most potent endogenous vasoconstrictor in mammals, promoting cardiovascular remodelling, cardiac fibrosis, and cardiomyocyte hypertrophy. It is also involved in other physiological and pathological activities, including neurosecretory effects, insulin resistance, atherosclerosis, kidney disease, and carcinogenic effects. Moreover, it is a notable player in the process of inflammatory injury, which leads to the development of inflammatory diseases. Urotensin‐II/UTR expression stimulates the accumulation of monocytes and macrophages, which promote the adhesion molecules expression, chemokines activation and release of inflammatory cytokines at inflammatory injury sites. Therefore, urotensin‐II turns out to be an important therapeutic target for the treatment options and management of associated diseases. The main downstream signaling pathways mediated through this urotensin‐II /UTR system are RhoA/ROCK, MAPKs and PI3K/AKT. Due to the importance of urotensin‐II systems in biomedicine, we consolidated a network map of urotensin‐II /UTR signaling. The described signaling map comprises 33 activation/inhibition events, 31 catalysis events, 15 molecular associations, 40 gene regulation events, 60 types of protein expression, and 11 protein translocation events. The urotensin‐II signaling pathway map is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway:WP5158). The availability of comprehensive urotensin‐II signaling in the public resource will help understand the regulation and function of this pathway in normal and pathological conditions. We believe this resource will provide a platform to the scientific community in facilitating the identification of novel therapeutic drug targets for diseases associated with urotensin‐II signaling.

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A network map of apelin-mediated signaling

Cited by 9 publications

References 62 publications

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids

Apelin receptor inhibition in ischemia-reperfused mouse hearts protected by endogenous n-3 polyunsaturated fatty acids

The network map of Elabela signaling pathway in physiological and pathological conditions

The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions

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