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Discovery and characterization of alamandine, a novel component of the renin-angiotensin system

Item Type:Article
Title:Discovery and characterization of alamandine, a novel component of the renin-angiotensin system
Creators Name:Lautner, R.Q. and Villela, D.C. and Fraga-Silva, R.A. and Silva, N.C. and Verano-Braga, T. and Costa-Fraga, F. and Jankowski, J. and Jankowski, V. and De Sousa, F.B. and Alzamora, A.C. and Soares, E.R. and Barbosa, C.M. and Kjeldsen, F. and Oliveira, A.C. and Braga, J.F. and Savergnini, S.Q. and Etelvino, G.M. and Bastos Peluso, A.A. and Passos-Silva, D.G. and Ferreira, A.J. and Alves, F. and Martins, A.S. and Raizada, M.K. and Paula, R.D. and Motta-Santos, D. and Klempin, F. and Pimenta, A.M.C. and Alenina, N. and Sinisterra, R.D.M. and Bader, M. and Campagnole-Santos, M.J. and Santos, R.A.S.
Abstract:Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte and water balance. Here we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of ACE2 angiotensin A, or directly from angiotensin-(1-7). Objective: To characterize a novel component of the RAS, alamandine. Methods and Results: Using Mass Spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, anti-fibrosis, anti-hypertensive and central effects. Interestingly, our data reveals that its actions are independent of the known vasodilator receptors of the RAS, Mas and AT2. Rather, we demonstrate that alamandine acts through the Mas-related G-Protein coupled receptor, MrgD. Binding of alamandine to MrgD is blocked by D-Pro7-Ang-(1-7), the MrgD ligand beta-alanine and PD-123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/beta-hydroxypropyl cyclodextrin produced a long-lasting anti-hypertensive effect in spontaneously hypertensive rats and anti-fibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or anti-proliferative effect in human tumoral cell lines. Conclusions: The identification of these two novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS, and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.
Keywords:Angiotensin II, Antihypertensive Treatment, Cardiovascular System, Hypertension, Renin–Angiotensin System, Vasoactive Peptides, Vascular Reactivity, Animals, Rats
Source:Circulation Research
Publisher:American Heart Association
Page Range:1104-1111
Date:12 April 2013
Official Publication:https://doi.org/10.1161/CIRCRESAHA.113.301077
PubMed:View item in PubMed

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