title: Discovery and characterization of alamandine: a novel component of the renin-angiotensin system.
abstract: BACKGROUND
  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.
  
  
  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-Pro(7)-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.
authors: Department of Physiology and Biophysics, National Institute of Science and Technology in Nanobiopharmaceutics, UFMG, Minas Gerais, Brazil.
authors: Roberto Queiroga
authors: RQ
authors: Lautner
authors: Daniel C
authors: DC
authors: Villela
authors: Rodrigo A
authors: RA
authors: Fraga-Silva
authors: Neiva
authors: N
authors: Silva
authors: Thiago
authors: T
authors: Verano-Braga
authors: Fabiana
authors: F
authors: Costa-Fraga
authors: Joachim
authors: J
authors: Jankowski
authors: Vera
authors: V
authors: Jankowski
authors: Frederico
authors: F
authors: Sousa
authors: Andreia
authors: A
authors: Alzamora
authors: Everton
authors: E
authors: Soares
authors: Claudiane
authors: C
authors: Barbosa
authors: Frank
authors: F
authors: Kjeldsen
authors: Aline
authors: A
authors: Oliveira
authors: Janaina
authors: J
authors: Braga
authors: Silvia
authors: S
authors: Savergnini
authors: Gisele
authors: G
authors: Maia
authors: Antonio Bastos
authors: AB
authors: Peluso
authors: Danielle
authors: D
authors: Passos-Silva
authors: Anderson
authors: A
authors: Ferreira
authors: Fabiana
authors: F
authors: Alves
authors: Almir
authors: A
authors: Martins
authors: Mohan
authors: M
authors: Raizada
authors: Renata
authors: R
authors: Paula
authors: Daisy
authors: D
authors: Motta-Santos
authors: Friederike
authors: F
authors: Klempin
authors: Friederike
authors: F
authors: Kemplin
authors: Adriano
authors: A
authors: Pimenta
authors: Natalia
authors: N
authors: Alenina
authors: Ruben
authors: R
authors: Sinisterra
authors: Michael
authors: M
authors: Bader
authors: Maria Jose
authors: MJ
authors: Campagnole-Santos
authors: Robson A S
authors: RA
authors: Santos
mesh_terms: D000803:Angiotensin I / Q000737:chemistry* / Q000502:physiology; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000737:chemistry / Q000502:physiology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000737:chemistry* / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry* / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011918:Rats, Inbred SHR; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D000959:Antihypertensive Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C581752:alamandine; D000804:Angiotensin II; C032651:angiotensin II, Sar(1)-Ile(5)-; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)