Decarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamics
| Autor: | Thomas Walther, Esther Sala, Kinga Gebolys, Jenny Eichhorst, Óscar Villacañas, Maura Naughton, Anja Tetzner |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology chemistry.chemical_classification G protein Mas receptor HEK 293 cells Peptide Transfection 030204 cardiovascular system & hematology Amino acid 03 medical and health sciences Dose–response relationship 030104 developmental biology 0302 clinical medicine chemistry Dose-response curve Renin–angiotensin system MrgD receptor cardiovascular system G-proteins Renin-angiotensin system Receptor hormones hormone substitutes and hormone antagonists Ala1-Angiotensin-(1–7) |
| Zdroj: | European Journal of Pharmacology. 833:116-123 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2018.05.031 |
| Popis: | 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 AngII. 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 as only stimulating 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 was 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 builds the basis for the design of more potent and efficient Ang-(1-7) analogues for therapeutic intervention in a rapidly growing number of diseases. |
| Databáze: | OpenAIRE |
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