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1.
Eur J Pharmacol ; 833: 116-123, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29792841

RESUMO

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.


Assuntos
Angiotensina I/metabolismo , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Células Cultivadas , AMP Cíclico/metabolismo , Descarboxilação , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Camundongos Knockout , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/genética
2.
Hypertension ; 68(1): 185-94, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27217404

RESUMO

Angiotensin (Ang)-(1-7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin-angiotensin system. Although it is well accepted that the G-protein-coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang-(1-7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1-7) allowing confirmation as well as discovery of the heptapeptide's receptors. Ang-(1-7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1-7). Moreover, we identified the G-protein-coupled receptor MrgD as a second receptor for Ang-(1-7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in both Mas and MrgD Mice deficient in MrgD showed an impaired hemodynamic response after Ang-(1-7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin-angiotensin system, by identifying a second receptor for Ang-(1-7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319.


Assuntos
Adenilil Ciclases/metabolismo , Angiotensina I/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipertensão/enzimologia , Fragmentos de Peptídeos/farmacologia , Adenilil Ciclases/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Células HEK293/efeitos dos fármacos , Células HEK293/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfotransferases/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sensibilidade e Especificidade
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