Discovery and Characterization of Alamandine A Novel Component of the Renin–Angiotensin System
Roberto Queiroga Lautner,Daniel C. Villela,Rodrigo A. Fraga-Silva,Neiva Caldeira Silva,Thiago Verano-Braga,Fabiana P. Costa-Fraga,Joachim Jankowski,Vera Jankowski,Frederico B. De Sousa,Andréia Carvalho Alzamora,Everton Rocha Soares,Claudiane Maria Barbosa,Frank Kjeldsen,Aline C. Oliveira,Janaina F Braga,Silvia Q Savergnini,Gisele Maia,Antonio A B Peluso,Danielle G. Passos-Silva,Anderson J. Ferreira,Fabiana Alves,Almir S. Martins,Mohan K. Raizada,Renata D. Paula,Daisy Motta-Santos,Friederike Kemplin,Adriano Marçal Pimenta,Natalia Alenina,Rubén D. Sinisterra,Michael Bader,Maria José Campagnole-Santos,Robson A.S. Santos +31 more
TLDR
Alamandine produces several physiological actions that resemble those produced by angiotensin-(1–7), including vasodilation, antifibrosis, antihypertensive, and central effects and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.Abstract:
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-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.read more
Citations
More filters
Journal ArticleDOI
The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)
Robson A.S. Santos,Walkyria O. Sampaio,Andréia Carvalho Alzamora,Daisy Motta-Santos,Natalia Alenina,Michael Bader,Maria José Campagnole-Santos +6 more
TL;DR: This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.
Journal ArticleDOI
Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology.
Steven J. Forrester,George W. Booz,Curt D. Sigmund,Thomas M. Coffman,Tatsuo Kawai,Victor Rizzo,Rosario Scalia,Satoru Eguchi +7 more
TL;DR: It is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
Journal ArticleDOI
The Concise Guide to PHARMACOLOGY 2013/14: G Protein‐Coupled Receptors
Stephen P.H. Alexander,Helen E. Benson,Elena Faccenda,Adam J. Pawson,Joanna L. Sharman,Michael Spedding,John A. Peters,Anthony J. Harmar +7 more
Journal ArticleDOI
Circulating MicroRNAs as Novel Biomarkers for Platelet Activation
Peter Willeit,Anna Zampetaki,Katarzyna A. Dudek,Dorothee Kaudewitz,Alice King,Nicholas S. Kirkby,Roxanne Crosby-Nwaobi,Marianna Prokopi,Ignat Drozdov,Sarah R. Langley,Sobha Sivaprasad,Hugh S. Markus,Jane A. Mitchell,Timothy D. Warner,Stefan Kiechl,Manuel Mayr +15 more
TL;DR: A substantial platelet contribution to the circulating miRNA pool is demonstrated and miRNAs responsive to antiplatelet therapy are identified, highlighting that anti platelet therapy and preparation of blood samples could be confounding factors in case-control studies relating plasma mi RNAs to cardiovascular disease.
Journal ArticleDOI
Counter-regulatory renin-angiotensin system in cardiovascular disease
María Paz Ocaranza,Jaime A. Riquelme,Lorena García,Jorge E. Jalil,Mario Chiong,Robson A.S. Santos,Sergio Lavandero,Sergio Lavandero +7 more
TL;DR: The latest insights are provided into the complexity and interplay of the components of the non-canonical renin–angiotensin system, and the function and therapeutic potential of targeting this system to treat cardiovascular disease.
References
More filters
Journal ArticleDOI
A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9
Mary Donoghue,Frank Y. Hsieh,Elizabeth Baronas,Kevin Godbout,Michael Gosselin,Nancy E. Stagliano,Michael J. Donovan,Betty Woolf,Keith E. Robison,Raju Jeyaseelan,Roger E. Breitbart,Susan L. Acton +11 more
TL;DR: The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney.
Journal ArticleDOI
A Human Homolog of Angiotensin-converting Enzyme CLONING AND FUNCTIONAL EXPRESSION AS A CAPTOPRIL-INSENSITIVE CARBOXYPEPTIDASE
Sarah R. Tipnis,Nigel M. Hooper,Ralph J. Hyde,Eric H. Karran,Gary Christie,Anthony J. Turner +5 more
TL;DR: A novel human zinc metalloprotease that has considerable homology to human angiotensin-converting enzyme (ACE) (40% identity and 61% similarity) has been identified.
Journal ArticleDOI
Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.
Robson A.S. Santos,Ana Cristina Simões e Silva,Christine Maric,Denise M. R. Silva,Raquel Pillar Machado,Insa de Buhr,Silvia Heringer-Walther,Sérgio Veloso Brant Pinheiro,Myriam Teresa Lopes,Michael Bader,Elizabeth Pereira Mendes,Virgina Soares Lemos,Maria José Campagnole-Santos,Heinz-Peter Schultheiss,Robert C. Speth,Thomas Walther +15 more
TL;DR: Findings identify Mas as a functional receptor for Ang-(1–7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.
Journal ArticleDOI
Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin
Geneviève Nguyen,Françoise Delarue,Céline Burcklé,Latifa Bouzhir,Thomas Giller,Jean-Daniel Sraer +5 more
TL;DR: The expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein is reported, the first described for an aspartyl protease.
Journal ArticleDOI
The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer
Masatoshi Nakajima,Howard G. Hutchinson,Masahiko Fujinaga,Wataru Hayashida,Ryuichi Morishita,Lunan Zhang,Masatsugu Horiuchi,Richard E. Pratt,Victor J. Dzau +8 more
TL;DR: Results suggest that the AT2 receptor exerts an antiproliferative effect, counteracting the growth action of AT1 receptor.
Related Papers (5)
Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.
Robson A.S. Santos,Ana Cristina Simões e Silva,Christine Maric,Denise M. R. Silva,Raquel Pillar Machado,Insa de Buhr,Silvia Heringer-Walther,Sérgio Veloso Brant Pinheiro,Myriam Teresa Lopes,Michael Bader,Elizabeth Pereira Mendes,Virgina Soares Lemos,Maria José Campagnole-Santos,Heinz-Peter Schultheiss,Robert C. Speth,Thomas Walther +15 more
Angiotensin-converting enzyme 2 is an essential regulator of heart function
Michael A. Crackower,Renu Sarao,Renu Sarao,Gavin Y. Oudit,Gavin Y. Oudit,Chana Yagil,Ivona Kozieradzki,Ivona Kozieradzki,Sam E. Scanga,Antonio J. Oliveira-dos-Santos,Joan da Costa,Liyong Zhang,York Pei,James W. Scholey,Carlos M. Ferrario,Armen S. Manoukian,Mark C. Chappell,Peter H. Backx,Peter H. Backx,Yoram Yagil,Josef M. Penninger +20 more