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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Williams, Thomas L 
Nyimanu, Duuamene 
Kuc, Rhoda E 
Foster, Richard 
Glen, Robert C 

Abstract

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.

Description

Keywords

GPCR, MM07, animal model, apelin, apelin receptor, biased signalling, cardiovascular, pulmonary hypertension

Journal Title

Front Pharmacol

Conference Name

Journal ISSN

1663-9812
1663-9812

Volume Title

Publisher

Frontiers Media S.A.
Sponsorship
British Heart Foundation (TG/18/4/33770)
Wellcome Trust (203814/Z/16/Z)
British Heart Foundation (TG/18/4/33770) and Wellcome Trust Programme in Metabolic and Cardiovascular Disease (203814/Z/16/A).