A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension.
Kuc, Rhoda E
British journal of pharmacology
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Yang, P., Read, C., Kuc, R. E., Nyimanu, D., Williams, T., Crosby, A., Buonincontri, G., et al. (2019). A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension.. British journal of pharmacology, 176 (9), 1206-1221. https://doi.org/10.1111/bph.14603
Background and Purpose: Apelin is an endogenous vasodilatory and inotropic peptide that is down-regulated in human pulmonary arterial hypertension, however, the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein-biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced - arrestin mediated receptor internalisation with chronic use. Experimental Approach: Male Sprague-Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily intraperitoneal injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation and apoptosis of human pulmonary artery endothelial cells was investigated. Key Results: MM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline-induced changes in cardiac structure and function, including right ventricular end-systolic and end- diastolic volumes, ejection fraction and left ventricular end-diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline-induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial nitric oxide synthase phosphorylation and expression, promoted proliferation and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro. Conclusion and Implications: Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.
Animals, Rats, Rats, Sprague-Dawley, Disease Models, Animal, Monocrotaline, Male, Apelin Receptors, Pulmonary Arterial Hypertension
the Medical Research Council MC_PC_14116 [to APD] Wellcome Trust [107715/Z/15/Z to APD], Programme in Metabolic and Cardiovascular Disease [096822/Z/11/Z to PY; 203814/Z/16/A to TLW], Parke Davis Fellowship [to PY], British Heart Foundation [FS/14/59/31282 to CR] and in part by the National Institute for Health Research Cambridge Biomedical Research Centre.
Wellcome Trust (096822/Z/11/A)
WELLCOME TRUST (107715/Z/15/Z)
British Heart Foundation (TG/18/4/33770)
British Heart Foundation (FS/06/017)
British Heart Foundation (unknown)
British Heart Foundation (FS/14/59/31282)
Wellcome Trust (10573/Z/14/Z)
Wellcome Trust (096822/Z/11/Z)
MRC (MC_PC_14116 v2)
Wellcome Trust (203814/Z/16/Z)
British Heart Foundation (RG/13/4/30107)
British Heart Foundation (PG/13/91/30579)
External DOI: https://doi.org/10.1111/bph.14603
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289114