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

Authors

• 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

Recommended Citation

Shimada, Kenji; Furukawa, Hajime; Wada, Kosuke; Wei, Yuan; Tada, Yoshiteru; Kuwabara, Atsushi; Shikata, Fumiaki; Kanematsu, Yasuhisa; Lawton, Michael T.; Kitazato, Keiko T.; Nagahiro, Shinji; and Hashimoto, Tomoki, "Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice" (2015). Neurosurgery. 1112.
https://scholar.barrowneuro.org/neurosurgery/1112