Discovery and characterization of alamandine: A novel component of the renin-angiotensin system
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Discovery and characterization of alamandine : A novel component of the renin-angiotensin system. / Lautner, Roberto Queiroga; Villela, Daniel C.; Fraga-Silva, Rodrigo A.; Silva, Neiva; Verano-Braga, Thiago; Costa-Fraga, Fabiana; Jankowski, Joachim; Jankowski, Vera; Sousa, Frederico; Alzamora, Andreia; Soares, Everton; Barbosa, Claudiane; Kjeldsen, Frank; Oliveira, Aline; Braga, Janaina; Savergnini, Silvia; Maia, Gisele; Peluso, Antonio Bastos; Passos-Silva, Danielle; Ferreira, Anderson; Alves, Fabiana; Martins, Almir; Raizada, Mohan; Paula, Renata; Motta-Santos, Daisy; Kemplin, Friederike; Pimenta, Adriano; Alenina, Natalia; Sinisterra, Ruben; Bader, Michael; Campagnole-Santos, Maria Jose; Santos, Robson A.S.
In: Circulation Research, Vol. 112, No. 8, 12.04.2013, p. 1104-1111.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Discovery and characterization of alamandine
T2 - A novel component of the renin-angiotensin system
AU - Lautner, Roberto Queiroga
AU - Villela, Daniel C.
AU - Fraga-Silva, Rodrigo A.
AU - Silva, Neiva
AU - Verano-Braga, Thiago
AU - Costa-Fraga, Fabiana
AU - Jankowski, Joachim
AU - Jankowski, Vera
AU - Sousa, Frederico
AU - Alzamora, Andreia
AU - Soares, Everton
AU - Barbosa, Claudiane
AU - Kjeldsen, Frank
AU - Oliveira, Aline
AU - Braga, Janaina
AU - Savergnini, Silvia
AU - Maia, Gisele
AU - Peluso, Antonio Bastos
AU - Passos-Silva, Danielle
AU - Ferreira, Anderson
AU - Alves, Fabiana
AU - Martins, Almir
AU - Raizada, Mohan
AU - Paula, Renata
AU - Motta-Santos, Daisy
AU - Kemplin, Friederike
AU - Pimenta, Adriano
AU - Alenina, Natalia
AU - Sinisterra, Ruben
AU - Bader, Michael
AU - Campagnole-Santos, Maria Jose
AU - Santos, Robson A.S.
PY - 2013/4/12
Y1 - 2013/4/12
N2 - 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 angiotensin-converting enzyme-2 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, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro7-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. CONCLUSIONS: The identification of these 2 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.
AB - 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 angiotensin-converting enzyme-2 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, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro7-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. CONCLUSIONS: The identification of these 2 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.
KW - angiotensin II
KW - antihypertensive treatment
KW - cardiovascular system
KW - hypertension
KW - renin.angiotensin system
KW - vascular reactivity
KW - vasoactive peptides
UR - http://www.scopus.com/inward/record.url?scp=84876407858&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.113.301077
DO - 10.1161/CIRCRESAHA.113.301077
M3 - Journal article
C2 - 23446738
AN - SCOPUS:84876407858
VL - 112
SP - 1104
EP - 1111
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 8
ER -
ID: 321474385