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- Title
The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.
- Authors
Williams, Thomas L.; Nyimanu, Duuamene; Kuc, Rhoda E.; Foster, Richard; Glen, Robert C.; Maguire, Janet J.; Davenport, Anthony P.
- 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.
- Subjects
ENDOTHELINS; PULMONARY arterial hypertension; RIGHT ventricular hypertrophy; APELIN; G protein coupled receptors; SYSTOLIC blood pressure; VASCULAR remodeling; ENDOTHELIN receptors
- Publication
Frontiers in Pharmacology, 2024, p1
- ISSN
1663-9812
- Publication type
Article
- DOI
10.3389/fphar.2024.1369489