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Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia.

Abstract There is an emerging consensus that hyperhomocysteinemia is an independent risk factor for cerebral vascular disease and that homocysteine-lowering therapy protects from ischemic stroke. However, the mechanisms by which hyperhomocysteinemia produces abnormalities of cerebral vascular structure and function remain largely undefined. Our objective in this study was to define the mechanistic role of superoxide in hyperhomocysteinemia-induced cerebral vascular dysfunction and hypertrophy. Unlike previous studies, our experimental design included a genetic approach to alter superoxide levels by using superoxide dismutase 1 (SOD1)-deficient mice fed a high methionine/low folate diet to produce hyperhomocysteinemia. In wild-type mice, the hyperhomocysteinemic diet caused elevated superoxide levels and impaired responses to endothelium-dependent vasodilators in cerebral arterioles, and SOD1 deficiency compounded the severity of these effects. The cross-sectional area of the pial arteriolar wall was markedly increased in mice with SOD1 deficiency, and the hyperhomocysteinemic diet sensitized SOD1-deficient mice to this hypertrophic effect. Analysis of individual components of the vascular wall demonstrated a significant increase in the content of smooth muscle and elastin. We conclude that superoxide is a key driver of both cerebral vascular hypertrophy and vasomotor dysfunction in this model of dietary hyperhomocysteinemia. These findings provide insight into the mechanisms by which hyperhomocysteinemia promotes cerebral vascular disease and ischemic stroke.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 28414812
OWN - NLM
STAT- In-Process
DA  - 20170417
LR  - 20170417
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and
      vascular dysfunction in hyperhomocysteinemia.
PG  - e0175732
LID - 10.1371/journal.pone.0175732 [doi]
AB  - There is an emerging consensus that hyperhomocysteinemia is an independent risk
      factor for cerebral vascular disease and that homocysteine-lowering therapy
      protects from ischemic stroke. However, the mechanisms by which
      hyperhomocysteinemia produces abnormalities of cerebral vascular structure and
      function remain largely undefined. Our objective in this study was to define the 
      mechanistic role of superoxide in hyperhomocysteinemia-induced cerebral vascular 
      dysfunction and hypertrophy. Unlike previous studies, our experimental design
      included a genetic approach to alter superoxide levels by using superoxide
      dismutase 1 (SOD1)-deficient mice fed a high methionine/low folate diet to
      produce hyperhomocysteinemia. In wild-type mice, the hyperhomocysteinemic diet
      caused elevated superoxide levels and impaired responses to endothelium-dependent
      vasodilators in cerebral arterioles, and SOD1 deficiency compounded the severity 
      of these effects. The cross-sectional area of the pial arteriolar wall was
      markedly increased in mice with SOD1 deficiency, and the hyperhomocysteinemic
      diet sensitized SOD1-deficient mice to this hypertrophic effect. Analysis of
      individual components of the vascular wall demonstrated a significant increase in
      the content of smooth muscle and elastin. We conclude that superoxide is a key
      driver of both cerebral vascular hypertrophy and vasomotor dysfunction in this
      model of dietary hyperhomocysteinemia. These findings provide insight into the
      mechanisms by which hyperhomocysteinemia promotes cerebral vascular disease and
      ischemic stroke.
FAU - Dayal, Sanjana
AU  - Dayal S
AD  - Department of Internal Medicine, University of Iowa Carver College of Medicine,
      Iowa City, Iowa, United States of America.
FAU - Baumbach, Gary L
AU  - Baumbach GL
AD  - Department of Pathology, University of Iowa Carver College of Medicine, Iowa
      City, Iowa, United States of America.
FAU - Arning, Erland
AU  - Arning E
AD  - Baylor Institute of Metabolic Disease, Dallas, Texas, United States of America.
FAU - Bottiglieri, Teodoro
AU  - Bottiglieri T
AD  - Baylor Institute of Metabolic Disease, Dallas, Texas, United States of America.
FAU - Faraci, Frank M
AU  - Faraci FM
AD  - Department of Internal Medicine, University of Iowa Carver College of Medicine,
      Iowa City, Iowa, United States of America.
AD  - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa
      City, Iowa, United States of America.
FAU - Lentz, Steven R
AU  - Lentz SR
AD  - Department of Internal Medicine, University of Iowa Carver College of Medicine,
      Iowa City, Iowa, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170417
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/04/18 06:00
MHDA- 2017/04/18 06:00
CRDT- 2017/04/18 06:00
PHST- 2016/08/09 [received]
PHST- 2017/03/30 [accepted]
AID - 10.1371/journal.pone.0175732 [doi]
AID - PONE-D-16-31902 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 17;12(4):e0175732. doi: 10.1371/journal.pone.0175732.
      eCollection 2017.

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