Identification and Characterization of Alamandine-(1-5), a New Component of the Renin-Angiotensin System.
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Santos Robson A S, Dias Melissa Tainan Silva, Bessa Amanda de Sá Martins, Barros Carolina Fonseca, Itaborahy Matheus F, da Silva Filipe Alex, Gonçalves Sthefanie Chaves de Almeida, Rodrigues-Ribeiro Lucas, Ferraz Kamylle Silva, Davel Ana Paula, Nóbrega Natália, Silva Bruno Durante da, Scalzo Sérgio, Soares Pedro Alves, Dutra João Batista Rodrigues, Lula Ivana, Feng Isadora Zhong Liang Ferreira, Vieira-Machado Uri Flegler, de Godoy Ana Caroline Ventris, Monteiro Adelson Héric Alves, Eliezeck Marcos, Sanches Bruno, Monteiro André, Magalhães Gabriela, Soares Nícia Pedreira, Pereira Danilo Augusto Alves, Rezende Ribeiro Júlia, Dias-Pinto Maria Luiza, de Souza Leandro Eziquiel, Silva Amanda de A, Motta-Santos Daisy, Bader Michael, Alenina Natália, Capettini Luciano Dos Santos Aggum, Peliky Fontes Marco Antônio, Haibara Andrea Siqueira, Campos Vilella Daniel, Verano-Braga Thiago, Irigoyen Maria Claudia, Marins Fernanda Ribeiro, Castro Carlos Henrique, Simões-E-Silva Ana Cristina, Guatimosim Silvia, Leite M Fatima, Campagnole-Santos Maria José
Аннотация
METHODS: To accomplish this, we have used mass spectrometry (Matrix-assisted Laser Desorption/Ionization Time-of-Flight/Time-of-Flight mass spectrometry [MALDI/TOF/TOF], Liquid Chromatography-Tandem Mass Spectrometry [LC-MS/MS]) and several methodologies, including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely moving normotensive and spontaneously hypertensive rats, high-resolution echocardiography, central administration (intracerebroventricular infusion and microinjection in the insular cortex), cell culture (endothelial cells and G-protein-coupled receptors-transfected Chinese Hamster Ovary cells), and wild-type and Mas (Mas receptor proto-oncogene), MrgD (Mas-related G-protein-coupled receptor subtype D), or AT2 (angiotensin II type 2) receptor-deficient mice.
RESULTS: We show that Ala-(1-5) is present in the circulation of healthy humans and rodents and promotes many biological central and peripheral actions. A major role for ACE (angiotensin-converting enzyme) activity in the formation of Ala-(1-5) from alamandine in the circulation was observed using plasma samples from angiotensinogen-knockout mice. Ala-(1-5) increases baroreflex sensitivity and produces a long-lasting (≈6 hours) antihypertensive effect in spontaneously hypertensive rats, associated with a significant reduction in cardiac output. Additionally, Ala-(1-5) decreases inotropism in isolated perfused hearts and reduces contractility in cardiomyocytes. In Chinese Hamster Ovary cells-transfected cells, Ala-(1-5) can bind and stimulate NO production through all receptors from the renin-angiotensin system protective arm (Mas, MrgD, and AT2 receptors). On the other hand, the Ala-(1-5) effects on cardiomyocytes and mouse aortic rings were abolished only by MrgD genetic deletion, but not by Mas or AT2 receptor knockout.
CONCLUSIONS: Our data demonstrate that Ala-(1-5) is a newly identified peptide within the renin-angiotensin system, with strong blood pressure-lowering effects that vary in mechanisms of action among different tissues. Ala-(1-5) has distinct characteristics that differentiate it from the conventional renin-angiotensin system pathways responsible for reducing blood pressure.