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

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3358-3363
Number of pages6
JournalStroke
Volume43
Issue number12
DOIs
StatePublished - Dec 2012

Keywords

  • Aging
  • Angiotensin-converting enzyme 2
  • Cerebral arteries
  • Endothelium
  • Oxidative stress

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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    Peña-Silva, R. A., Chu, Y., Miller, J. D., Mitchell, I. J., Penninger, J. M., Faraci, F. M., & Heistad, D. D. (2012). Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke, 43(12), 3358-3363. https://doi.org/10.1161/STROKEAHA.112.667063