Apelin pathway in cardiovascular, kidney, and metabolic diseases: Therapeutic role of apelin analogs and apelin receptor agonists

Oliveira, Amanda Almeida de; Vergara, Ander; Wang, Xiaopu; Vederas, John C.; Oudit, Gavin Y.

doi:10.1016/j.peptides.2021.170697

Cited by 30 publications

(14 citation statements)

References 234 publications

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“…In the RV, genes involved in the apelin signalling pathway were enriched among the up-regulated genes. The apelin/apelin receptor system functions in various cardiovascular processes such as vascular homeostasis, angiogenesis, cardiomyocyte contractility, cardiac hypertrophic response, and even in early cardiac development [32,33]. Our data for the first time, report significantly up-regulated apelin signalling pathway in the RV of end-stage DCM hearts.…”

Section: Lv-and Rv-specific Pathological Genesmentioning

confidence: 52%

Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support

Parikh

Shah

Basu

et al. 2022

IJMS

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Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and evaluated changes in gene expression (mRNA) and regulation (microRNA/miRNA) following LVAD. LV and RV free-wall tissues were collected from end-stage DCM hearts with (n = 8) and without LVAD (n = 8). Non-failing control tissues were collected from donated hearts (n = 6). Gene expression (for mRNAs/miRNAs) was determined using microarrays. Our results demonstrate that immune response, oxygen homeostasis, and cellular physiological processes were the most enriched pathways among differentially expressed genes in both ventricles of end-stage DCM hearts. LV genes involved in circadian rhythm, muscle contraction, cellular hypertrophy, and extracellular matrix (ECM) remodelling were differentially expressed. In the RV, genes related to the apelin signalling pathway were affected. Following LVAD use, immune response genes improved in both ventricles; oxygen homeostasis and ECM remodelling genes improved in the LV and, four miRNAs normalized. We conclude that LVAD reduced the expression and induced additional transcriptomic changes of various mRNAs and miRNAs as an integral component of the reverse ventricular remodelling in a chamber-specific manner.

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Section: Lv-and Rv-specific Pathological Genesmentioning

confidence: 52%

Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support

Parikh

Shah

Basu

et al. 2022

IJMS

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“…Apelin is a peptide hormone that by activating its G-protein coupled receptor (ApelinR) exerts many biological functions and whose production is induced by muscle contraction [48]. A number of studies have demonstrated that apelin improves skeletal muscle mass and function, exerts cardioprotective effects and promotes energy expenditure [49]. In the ventricular tissue of patients with advanced HFrEF, increased [50] or unchanged apelin levels have been reported [51], while ApelinR levels are consistently decreased [50,51].…”

Section: Dysregulation Of Myokines In Hfmentioning

confidence: 99%

Revisiting skeletal myopathy and exercise training in heart failure: Emerging role of myokines

et al. 2023

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“…Apelin is an endogenous peptide ligand that targets the class A G protein-coupled apelin receptor ( O’Dowd et al, 1993 ; Tatemoto et al, 1998 ). Both apelin and the apelin receptor are widely expressed in various tissues and cell types, including endothelial cells, smooth muscle cells and cardiomyocytes, where they mediate vasodilatation and positive cardiac inotropy in health and disease ( Kleinz et al, 2005 ; Maguire et al, 2009 ; Marsault et al, 2019 ; Read et al, 2019 ; de Oliveira et al, 2022 ). Loss of BMPR2 in PAH is associated with an upregulation of the miR-130/301 miRNA family ( Bertero et al, 2014 ; 2018 ), causing a subsequent reduction in the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ), and reduced expression of apelin ( Alastalo et al, 2011 ; Yang et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan

Williams,

Nyimanu,

Kuc

et al. 2024

Front. Pharmacol.

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Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan.Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30 mg/kg), or MM07 (10 mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment.Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4 weeks of treatment.Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

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Apelin pathway in cardiovascular, kidney, and metabolic diseases: Therapeutic role of apelin analogs and apelin receptor agonists

Cited by 30 publications

References 234 publications

Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support

Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support

Revisiting skeletal myopathy and exercise training in heart failure: Emerging role of myokines

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan

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