Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice

Kenji Shimada, 1] Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA [2] Department of Neurosurgery, School of Medicine, The University of Tokushima, Tokushima City, Japan.
Hajime Furukawa, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
Kosuke Wada, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
Yuan Wei, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
Yoshiteru Tada, Department of Neurosurgery, School of Medicine, The University of Tokushima, Tokushima City, Japan.
Atsushi Kuwabara, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
Fumiaki Shikata, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
Yasuhisa Kanematsu, Department of Neurosurgery, School of Medicine, The University of Tokushima, Tokushima City, Japan.
Michael T. Lawton, Department of Neurological Surgery, University of California, San Francisco, California, USA.Follow
Keiko T. Kitazato, Department of Neurosurgery, School of Medicine, The University of Tokushima, Tokushima City, Japan.
Shinji Nagahiro, Department of Neurosurgery, School of Medicine, The University of Tokushima, Tokushima City, Japan.
Tomoki Hashimoto, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.Follow

Document Type

Article

Abstract

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.

Medical Subject Headings

Aneurysm, Ruptured (complications, genetics, pathology, prevention & control); Angiotensin I (therapeutic use); Angiotensin II (analogs & derivatives, therapeutic use); Angiotensin II Type 2 Receptor Blockers (therapeutic use); Animals; Brain (blood supply); Cerebral Arteries (drug effects, metabolism, pathology); Cytokines (analysis); Imidazoles (therapeutic use); Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments (therapeutic use); Pyridines (therapeutic use); RNA, Messenger (genetics); Receptor, Angiotensin, Type 2 (genetics); Subarachnoid Hemorrhage (complications, genetics, pathology, prevention & control)

Publication Date

3-12-2015

Publication Title

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

E-ISSN

1559-7016

Volume

35

Issue

7

First Page

1163

Last Page

8

PubMed ID

25757758

Digital Object Identifier (DOI)

10.1038/jcbfm.2015.30

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