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 -