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| Item Type: | Article |
|---|---|
| Title: | Identification and characterization of alamandine-(1-5), a new component of the renin-angiotensin system |
| Creators: |
Santos, Robson A.S.  ORCID: https://orcid.org/0000-0001-8738-5852, Dias, Melissa Tainan Silva, de Bessa, Amanda de Sá Martins ORCID: https://orcid.org/0000-0001-9806-4376, de Barros, Carolina Fonseca ORCID: https://orcid.org/0000-0002-1204-2596, Itaborahy, Matheus F., da Silva, Filipe Alex ORCID: https://orcid.org/0000-0002-1418-9591, Gonçalves, Sthefanie Chaves de Almeida ORCID: https://orcid.org/0000-0003-2210-0902, Rodrigues-Ribeiro, Lucas ORCID: https://orcid.org/0000-0002-4011-637X, Ferraz, Kamylle Silva ORCID: https://orcid.org/0009-0003-8186-8476, Davel, Ana Paula ORCID: https://orcid.org/0000-0002-9862-4262, Nóbrega, Natália, Silva, Bruno Durante da, Scalzo, Sérgio ORCID: https://orcid.org/0000-0002-1496-878X, Soares, Pedro Alves ORCID: https://orcid.org/0000-0002-1183-7610, Dutra, João Batista Rodrigues ORCID: https://orcid.org/0000-0002-9800-4979, Lula, Ivana ORCID: https://orcid.org/0009-0006-3987-5738, Feng, Isadora Zhong Liang Ferreira, Vieira-Machado, Uri Flegler, de Godoy, Ana Caroline Ventris ORCID: https://orcid.org/0000-0003-4789-1691, Monteiro, Adelson Héric Alves ORCID: https://orcid.org/0009-0001-8334-1219, Eliezeck, Marcos ORCID: https://orcid.org/0000-0001-8942-6822, Sanches, Bruno ORCID: https://orcid.org/0000-0002-9029-609X, Monteiro, André ORCID: https://orcid.org/0000-0002-3632-9145, Magalhães, Gabriela ORCID: https://orcid.org/0009-0009-0875-5591, Soares, Nícia Pedreira, Pereira, Danilo Augusto Alves ORCID: https://orcid.org/0009-0001-4111-7008, Rezende Ribeiro, Júlia ORCID: https://orcid.org/0009-0003-1761-7250, Dias-Pinto, Maria Luiza ORCID: https://orcid.org/0009-0007-2625-5836, de Souza, Leandro Eziquiel ORCID: https://orcid.org/0000-0001-8279-5422, Silva, Amanda de A. ORCID: https://orcid.org/0009-0007-3226-8107, Motta-Santos, Daisy ORCID: https://orcid.org/0000-0002-3265-7838, Bader, Michael ORCID: https://orcid.org/0000-0003-4780-4164, Alenina, Natália ORCID: https://orcid.org/0000-0002-6071-5433, Capettini, Luciano Dos Santos Aggum ORCID: https://orcid.org/0000-0002-6487-9558, Peliky Fontes, Marco Antônio ORCID: https://orcid.org/0000-0003-4525-3565, Haibara, Andrea Siqueira ORCID: https://orcid.org/0000-0002-6783-8583, Campos Vilella, Daniel ORCID: https://orcid.org/0000-0002-2510-9817, Verano-Braga, Thiago ORCID: https://orcid.org/0000-0002-7083-2588, Irigoyen, Maria Claudia ORCID: https://orcid.org/0000-0003-2097-3662, Marins, Fernanda Ribeiro ORCID: https://orcid.org/0000-0003-2735-5701, de Castro, Carlos Henrique ORCID: https://orcid.org/0000-0002-9510-1124, Simões-E-Silva, Ana Cristina ORCID: https://orcid.org/0000-0001-9222-3882, Guatimosim, Silvia, Leite, M. Fatima ORCID: https://orcid.org/0000-0001-9709-8865 and Campagnole-Santos, Maria José ORCID: https://orcid.org/0000-0001-9483-4206
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| Abstract: | BACKGROUND: The renin-angiotensin system comprises a biochemical cascade that hydrolyzes angiotensinogen into several different bioactive peptides, which can activate different receptors, promoting plenty of specific effects. This study aimed to evaluate the presence of the putative product of alamandine, the pentapeptide Ala-(1-5) (alamandine-[1-5]), in the circulation and its biological activity. METHODS: To accomplish this, we have used mass spectrometry (MALDI/TOF/TOF, LC-MS/MS) and several methodologies, including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely moving normotensive and SHR, high-resolution echocardiography, central administration (ICV infusion and microinjection in the insular cortex), cell culture (endothelial cells and G-protein-coupled receptors-transfected CHO cells), and wild-type and Mas (Mas receptor proto-oncogene), MrgD (Mas-related G-protein-coupled receptor subtype D), or AT(2) (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-KO mice. Ala-(1-5) increases baroreflex sensitivity and produces a long-lasting (≈6 hours) antihypertensive effect in SHR, associated with a significant reduction in cardiac output. Additionally, Ala-(1-5) decreases inotropism in isolated perfused hearts and reduces contractility in cardiomyocytes. In CHO-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. |
| Keywords: | Angiotensin A, Angiotensins, Hypertension, Insular Cortex, Mas1, Animals, Mice, Rats |
| Source: | Circulation Research |
| ISSN: | 0009-7330 |
| Publisher: | American Heart Association |
| Volume: | 138 |
| Number: | 1 |
| Page Range: | e326174 |
| Date: | 2 January 2026 |
| Official Publication: | https://doi.org/10.1161/circresaha.125.326174 |
| PubMed: | View item in PubMed |
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