Angiotensin II–Independent Angiotensin-(1–7) Formation in Rat Hippocampus: Involvement of Thimet Oligopeptidase

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 62; no. 5; pp. 879 - 885
• Main Authors: Pereira, Marilia G.A.G, Souza, Laura L, Becari, Christiane, Duarte, Diego A, Camacho, Fabio R.B, Oliveira, José Antônio C, Gomes, Marcelo D, Oliveira, Eduardo B, Salgado, Maria Cristina O, Garcia-Cairasco, Norberto, Costa-Neto, Claudio M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-11-2013; Lippincott Williams & Wilkins
• Subjects: Angiotensin I - biosynthesis; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Epilepsy - metabolism; Female; Hippocampus - metabolism; Medical sciences; Metalloendopeptidases - metabolism; Peptide Fragments - biosynthesis; Proto-Oncogene Proteins - metabolism; Rats; Rats, Wistar; Receptors, G-Protein-Coupled - metabolism; Renin-Angiotensin System - physiology; Rat; Peptide hormone; Central nervous system; Metalloendopeptidases; Cardiovascular disease; Encephalon; Octapeptide; renin―angiotensin system; Tumor; Angiotensin II; Biological receptor; Hypertension; Enzyme; Rodentia; Thimet oligopeptidase; Mass; Peptidases; Vertebrata; Renin angiotensin system; Mammalia; Animal; angiotensin-(1―7); Hydrolases; Circulatory system; Formation; angiotensin-(1―7) receptor Mas; angiotensins; Hippocampus; angiotensin-(1–7); renin–angiotensin system; angiotensin-(1–7) receptor Mas; central nervous system; thimet oligopeptidase
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.113.01613

The involvement and relevance of the renin–angiotensin system have been established clearly in cardiovascular diseases, and renin–angiotensin system involvement has also been investigated extensively in the central nervous system. Angiotensin II acts classically by binding to the AT1 and AT2 receptors. However, other pathways within the renin–angiotensin system have been described more recently, such as one in which angiotensin-(1–7) (Ang-(1–7)) binds to the receptor Mas. In the central nervous system specifically, it has been reported that this heptapeptide is involved in learning and memory processes that occur in central limbic regions, such as the hippocampus. Therefore, this prompted us to investigate the possible role of the Ang-(1–7)–receptor Mas pathway in epileptic seizures, which are also known to recruit limbic areas. In the present study, we show that Ang-(1–7) is the main metabolite of angiotensin I in rat hippocampi, and, strikingly, that thimet oligopeptidase is the main enzyme involved in the generation of Ang-(1–7). Furthermore, elevations in the levels of thimet oligopeptidase, Ang-(1–7), and of receptor Mas transcripts are observed in chronically stimulated epileptic rats, which suggest that the thimet oligopeptidase–Ang-(1–7)–receptor Mas axis may have a functional relevance in the pathophysiology of these animals. In summary, our data, which describe a new preferential biochemical pathway for the generation of Ang-(1–7) in the central nervous system and an increase in the levels of various elements of the related thimet oligopeptidase–Ang-(1–7)–receptor Mas pathway, unveil potential new roles of the renin–angiotensin system in central nervous system pathophysiology.