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Published on: September 28, 2015
Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice
Ricardo A Peña Silva1, David K Kung2, Ian J Mitchell2
1From the Departments of Internal Medicine (R.A.P.S., I.J.M., F.M.F., D.D.H.), Pharmacology (F.M.F., D.D.H.), and Neurosurgery (D.K.K., D.M.H.), University of Iowa; Facultad de Medicina, Universidad de los Andes, Bogotá, Colombia (R.A.P.S.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (N.A., M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Minas Gerais, Brazil (R.A.S.S.). rpena@uniandes.edu.co david-hasan@uiowa.edu.
Abstract:
Angiotensin II (Ang II) stimulates vascular inflammation, oxidative stress, and formation and rupture of intracranial aneurysms in mice. Because Ang 1-7 acts on Mas receptors and generally counteracts deleterious effects of Ang II, we tested the hypothesis that Ang 1-7 attenuates formation and rupture of intracranial aneurysms. Intracranial aneurysms were induced in wild-type and Mas receptor-deficient mice using a combination of Ang II-induced hypertension and intracranial injection of elastase in the basal cistern. Mice received elastase+Ang II alone or a combination of elastase+Ang II+Ang 1-7. Aneurysm formation, prevalence of subarachnoid hemorrhage, mortality, and expression of molecules involved in vascular injury were assessed. Systolic blood pressure was similar in mice receiving elastase+Ang II (mean±SE, 148±5 mm Hg) or elastase+Ang II+Ang 1-7 (144±5 mm Hg). Aneurysm formation was also similar in mice receiving elastase+Ang II (89%) or elastase+Ang II+Ang 1-7 (84%). However, mice that received elastase+Ang II+Ang 1-7 had reduced mortality (from 64% to 36%; P<0.05) and prevalence of subarachnoid hemorrhage (from 75% to 48%; P<0.05). In cerebral arteries, expression of the inflammatory markers, Nox2 and catalase increased similarly in elastase+Ang II or elastase+Ang II+Ang 1-7 groups. Ang 1-7 increased the expression of cyclooxygenase-2 and decreased the expression of matrix metalloproteinase-9 induced by elastase+Ang II (P<0.05). In Mas receptor-deficient mice, systolic blood pressure, mortality, and prevalence of subarachnoid hemorrhage were similar (P>0.05) in groups treated with elastase+Ang II or elastase+Ang II+Ang 1-7. The expression of Mas receptor was detected by immunohistochemistry in samples of human intracranial arteries and aneurysms. In conclusion, without attenuating Ang II-induced hypertension, Ang 1-7 decreased mortality and rupture of intracranial aneurysms in mice through a Mas receptor-dependent pathway.
Insights
Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice. This protective effect is mediated by Mas receptors and does not alter blood pressure, highlighting a novel therapeutic pathway for aneurysm treatment.
Area of Science:
- Cardiovascular Research
- Neuroscience
- Pharmacology
Background:
- Angiotensin II (Ang II) is implicated in vascular inflammation and intracranial aneurysm (IA) development.
- Angiotensin 1-7 (Ang 1-7) counteracts many detrimental effects of Ang II via Mas receptors.
- The role of Ang 1-7 in IA formation and rupture remains to be fully elucidated.
Purpose of the Study:
- To investigate the hypothesis that Ang 1-7 attenuates the formation and rupture of intracranial aneurysms.
- To determine if Ang 1-7 exerts its effects through a Mas receptor-dependent mechanism.
Main Methods:
- Intracranial aneurysms were induced in wild-type and Mas receptor-deficient mice using Ang II-induced hypertension and elastase injection.
- Mice were treated with Ang II alone or in combination with Ang 1-7.
- Aneurysm formation, subarachnoid hemorrhage (SAH) prevalence, mortality, and molecular markers of vascular injury were assessed.
Main Results:
- Ang 1-7 treatment did not alter systolic blood pressure or aneurysm formation rates.
- However, Ang 1-7 significantly reduced mortality (64% to 36%) and SAH prevalence (75% to 48%) in wild-type mice.
- Ang 1-7 modulated the expression of inflammatory markers, cyclooxygenase-2, and matrix metalloproteinase-9, and these effects were absent in Mas receptor-deficient mice.
Conclusions:
- Angiotensin 1-7 confers protection against intracranial aneurysm rupture and associated mortality in a Mas receptor-dependent manner.
- These protective effects are independent of Ang II-induced hypertension.
- Ang 1-7 represents a potential therapeutic agent for managing intracranial aneurysms.
