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Simultaneous Measurement of Superoxide/Hydrogen Peroxide and NADH Production by Flavin-containing Mitochondrial Dehydrogenases
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Published on: February 24, 2018

Superoxide-dependent cerebrovascular effects of homocysteine

F Zhang1, A Slungaard, G M Vercellotti

  • 1Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, University of Minnesota Medical School, Minnesota 55455, USA.

The American Journal of Physiology
|June 25, 1998
PubMed

Insights

Elevated homocysteine impairs cerebrovascular function by generating superoxide radicals that scavenge nitric oxide (NO), a key regulator of cerebral blood flow (CBF). This study shows homocysteine-copper complexes reduce CBF and impair NO-mediated vasodilation.

Area of Science:

  • Neuroscience
  • Cardiovascular Research
  • Biochemistry

Background:

  • Elevated plasma homocysteine is a known risk factor for ischemic cerebrovascular diseases.
  • The precise mechanisms by which homocysteine affects cerebrovascular function remain incompletely understood.
  • Metal-catalyzed production of reactive oxygen species by homocysteine is a potential pathway for vascular impairment.

Purpose of the Study:

  • To investigate whether homocysteine, in the presence of copper ions (Cu2+), alters cerebral circulation reactivity.
  • To determine if the observed cerebrovascular effects of homocysteine-Cu2+ are dependent on superoxide (O-2) generation.

Main Methods:

  • Experiments were conducted on halothane-anesthetized rats with exposed parietal cortex superfused with Ringer solution.
  • Cerebrocortical blood flow (CBF) was monitored using laser-Doppler flowmetry.
  • Responses to hypercapnia, acetylcholine (ACh), S-nitroso-N-acetylpenicillamine (SNAP), and papaverine were assessed with and without homocysteine-Cu2+ and superoxide dismutase (SOD).

Main Results:

  • Superfusion with homocysteine-Cu2+ significantly reduced resting CBF and attenuated responses to hypercapnia, ACh, and the NO donor SNAP.
  • The vasodilator papaverine, which acts independently of NO, did not show attenuated responses.
  • Co-administration of superoxide dismutase (SOD) completely prevented the cerebrovascular effects of homocysteine-Cu2+, indicating a role for superoxide.

Conclusions:

  • Homocysteine-Cu2+ selectively impairs nitric oxide (NO)-related cerebrovascular responses, likely by superoxide-dependent scavenging of NO.
  • Superoxide radicals generated from homocysteine-Cu2+ may form peroxynitrite, leading to NO inactivation.
  • This O-2-mediated scavenging of NO represents a potential mechanism linking hyperhomocysteinemia to cerebrovascular disease pathogenesis.

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