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Original Contribution

Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging

Ricardo A. Peña-Silva, Yi Chu, Jordan D. Miller, Ian J. Mitchell, Josef M. Penninger, Frank M. Faraci, Donald D. Heistad
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https://doi.org/10.1161/STROKEAHA.112.667063
Stroke. 2012;STROKEAHA.112.667063
Originally published November 15, 2012
Ricardo A. Peña-Silva
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Yi Chu
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Jordan D. Miller
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Ian J. Mitchell
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Josef M. Penninger
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Frank M. Faraci
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Donald D. Heistad
From the Departments of Pharmacology (R.A.P.S., F.M.F., D.D.H.) and Internal Medicine (Y.C., I.J.M., F.M.F., D.D.H.), University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); and Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
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Abstract

Background and Purpose—Angiotensin II produces oxidative stress and endothelial dysfunction in cerebral arteries, and angiotensin II type I receptors may play a role in longevity and vascular aging. Angiotensin-converting enzyme type 2 (ACE2) converts angiotensin II to angiotensin (1–7) and thus, may protect against effects of angiotensin II. We hypothesized that ACE2 deficiency increases oxidative stress and endothelial dysfunction in cerebral arteries and examined the role of ACE2 in age-related cerebrovascular dysfunction.

Methods—Endothelial function, expression of angiotensin system components, NADPH oxidase subunits, and proinflammatory cytokines were examined in cerebral arteries from adult (12 months old) and old (24 months old) ACE2 knockout (KO) and wild-type (WT) mice. The superoxide scavenger tempol was used to examine the role of oxidative stress on endothelial function.

Results—Vasodilatation to acetylcholine was impaired in adult ACE2 KO (24±6% [mean±SE]) compared with WT mice (52±7%; P<0.05). In old mice, vasodilatation to acetylcholine was impaired in WT mice (29±6%) and severely impaired in ACE2 KO mice (7±5%). Tempol improved endothelial function in adult and old ACE2 KO and WT mice. Aging increased mRNA for tumor necrosis factor-α in WT mice, and significantly increased mRNA levels of NAPDH oxidase 2, p47phox, and Regulator of calcineurin 1 in both ACE2 KO and WT mice. mRNA levels of angiotensin system components did not change during aging.

Conclusions—ACE2 deficiency impaired endothelial function in cerebral arteries from adult mice and augmented endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging.

  • aging
  • angiotensin-converting enzyme 2
  • cerebral arteries
  • endothelium
  • oxidative stress
  • Received June 5, 2012.
  • Revision received September 18, 2012.
  • Accepted September 21, 2012.
  • © 2012 American Heart Association, Inc.

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    Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging
    Ricardo A. Peña-Silva, Yi Chu, Jordan D. Miller, Ian J. Mitchell, Josef M. Penninger, Frank M. Faraci and Donald D. Heistad
    Stroke. 2012;STROKEAHA.112.667063, originally published November 15, 2012
    https://doi.org/10.1161/STROKEAHA.112.667063

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    Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging
    Ricardo A. Peña-Silva, Yi Chu, Jordan D. Miller, Ian J. Mitchell, Josef M. Penninger, Frank M. Faraci and Donald D. Heistad
    Stroke. 2012;STROKEAHA.112.667063, originally published November 15, 2012
    https://doi.org/10.1161/STROKEAHA.112.667063
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