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Decarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamics
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Accepted Version
Date
2018-05-21
Authors
Tetzner, Anja
Naughton, Maura
Gebolys, Kinga
Eichhorst, Jenny
Sala, Esther
Villacañas, Óscar
Walther, Thomas
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier B.V.
Published Version
Abstract
The heptapeptide angiotensin (Ang)–(1–7) is part of the beneficial arm of the renin-angiotensin system. Ang-(1–7) has cardiovascular protective effects, stimulates regeneration, and opposes the often detrimental effects of Ang II. We recently identified the G protein-coupled receptors Mas and MrgD as receptors for the heptapeptide. Ala1-Ang-(1–7) (Alamandine), a decarboxylated form of Ang-(1–7), has similar vasorelaxant effects, but has been described to only stimulate MrgD. Therefore, this study aimed to characterise the consequences of the lack of the carboxyl group in amino acid 1 on intracellular signalling and to identify the receptor fingerprint for Ala1-Ang-(1–7). In primary endothelial and mesangial cells, Ala1-Ang-(1–7) elevated cAMP concentration. Dose response curves generated with Ang-(1–7) and Ala1-Ang-(1–7) significantly differed from each other, with a much lower EC50 and a bell-shape curve for Ala1-Ang-(1–7). We provided pharmacological proof that both, Mas and MrgD, are functional receptors for Ala1-Ang-(1–7). Consequently, in primary mesangial cells with genetic deficiency in both receptors the heptapeptide failed to increase cAMP concentration. As we previously described for Ang-(1–7), the Ala1-Ang-(1–7)-mediated cAMP increase in Mas/MrgD-transfected HEK293 cells and primary cells were blocked by the AT2 receptor blocker, PD123319. The very distinct dose-response curves for both heptapeptides could be explained by in silico modelling, electrostatic potential calculations, and an involvement of Galpha i for higher concentrations of Ala1-Ang-(1–7). Our results identify Ala1-Ang-(1–7) as a peptide with specific pharmacodynamic properties and build the basis for the design of more potent and efficient Ang-(1–7) analogues for therapeutic interventions in a rapidly growing number of diseases.
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Keywords
Dose-response curve , G-proteins , Mas receptor , MrgD receptor , Renin-angiotensin system , Ala1-Angiotensin-(1–7)
Citation
Tetzner, A., Naughton, M., Gebolys, K., Eichhorst, J., Sala, E., Villacañas, Ó and Walther, T. (2018) 'Decarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamics', European Journal of Pharmacology. doi:10.1016/j.ejphar.2018.05.031