title: Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice.
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.
authors.affiliation: From 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.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Peña Silva
authors.affiliation: From 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.).
authors.forename: David K
authors.initials: DK
authors.lastname: Kung
authors.affiliation: From 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.).
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Mitchell
authors.affiliation: From 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.).
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.affiliation: From 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.).
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: From 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.).
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.affiliation: From 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.).
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.affiliation: From 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.).
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
authors.affiliation: From 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Hasan
mesh_terms: D017542:Aneurysm, Ruptured / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D000803:Angiotensin I / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006801:Humans; D002532:Intracranial Aneurysm / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: angiotein (1–7); angiotensin (1–7) receptor Mas, human; hypertension; intracranial aneurysm; subarachnoid hemorrhage