Angiotensin-(1-5) is a potent endogenous angiotensin AT(2)-receptor agonist

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Item Type:	Preprint
Title:	Angiotensin-(1-5) is a potent endogenous angiotensin AT(2)-receptor agonist
Creators Name:	Souza-Silva, I.M., Peluso, A.A., Elsaafien, K., Nazarova, A.L., Assersen, K.B., Rodrigues-Ribeiro, L., Mohammed, M., Rodrigues, A.F., Nawrocki, A., Johansen, L.A., Jensen, P., de Kloet, A.D., Krause, E.G., DelBorgo, M., Maslov, I., Widdop, R.E., Santos, R.A., Bader, M., Larsen, M.R., Verano-Braga, T., Katritch, V., Sumners, C. and Steckelings, U.M.
Abstract:	BACKGROUND: The renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects. METHODS: The effect of Ang-(1-5) (1µM) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT(2)-receptor (AT(2)R) or the receptor Mas. A potential vasodilatory effect of Ang-(1-5) was tested in mouse mesenteric and human renal arteries by wire myography; the effect on blood pressure was evaluated in normotensive C57BL/6 mice by Millar catheter. These experiments were performed in the presence or absence of a range of antagonists or inhibitors or in AT(2)R-knockout mice. Binding of Ang-(1-5) to the AT(2)R was confirmed and the preferred conformations determined by in silico docking simulations. The signaling network of Ang-(1-5) was mapped by quantitative phosphoproteomics. RESULTS: Key findings included: (1) Ang-(1-5) induced activation of eNOS by changes in phosphorylation at (Ser1177)eNOS and (Tyr657)eNOS and thereby (2) increased NO release from HAEC and AT(2)R-transfected CHO cells, but not from Mas-transfected or non-transfected CHO cells. (3) Ang-(1-5) induced relaxation of preconstricted mouse mesenteric and human renal arteries and (4) lowered blood pressure in normotensive mice – effects which were respectively absent in arteries from AT(2)R-KO or in PD123319-treated mice and which were more potent than effects of the established AT(2)R-agonist C21. (5) According to in silico modelling, Ang-(1-5) binds to the AT(2)R in two preferred conformations, one differing substantially from where the first five amino acids within angiotensin II bind to the AT(2)R. (6) Ang-(1-5) modifies signaling pathways in a protective RAS-typical way and with relevance for endothelial cell physiology and disease. CONCLUSIONS: Ang-(1-5) is a potent, endogenous AT(2)R-agonist.
Keywords:	Angiotensin-(1-5), Angiotensin AT(2) Receptor, Phosphoproteomics, Nitric Oxide, Blood Pressure, Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2024.04.05.588367v2
Date:	18 April 2024
Official Publication:	https://doi.org/10.1101/2024.04.05.588367

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