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Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine

M C Stühlinger1, P S Tsao, J H Her

  • 1Section of Vascular Medicine, Stanford University, Stanford, California, USA.

Circulation
|November 21, 2001
PubMed

Insights

High homocysteine levels increase asymmetric dimethylarginine (ADMA) by inhibiting its degrading enzyme, DDAH. This finding explains how homocysteine impairs blood vessel function and nitric oxide synthesis.

Area of Science:

  • Biochemistry
  • Cardiovascular Science
  • Molecular Biology

Background:

  • Hyperhomocysteinemia is linked to cardiovascular disease and impaired endothelium-dependent vasodilation.
  • Elevated asymmetric dimethylarginine (ADMA) is a potential mechanism for cardiovascular risk factors affecting vascular function.
  • ADMA is an endogenous inhibitor of nitric oxide synthase (NOS).

Purpose of the Study:

  • To investigate whether homocysteine can increase ADMA levels.
  • To elucidate the mechanism by which homocysteine might affect ADMA.

Main Methods:

  • Exposure of endothelial and nonvascular cells to DL-homocysteine or L-methionine.
  • Measurement of ADMA concentration in cell culture medium.
  • Assessment of dimethylarginine dimethylaminohydrolase (DDAH) activity.
  • Evaluation of nitric oxide synthesis in endothelial cells and aortic segments.
  • In vitro studies using recombinant human DDAH.

Main Results:

  • Homocysteine increased ADMA levels in a dose- and time-dependent manner.
  • This increase in ADMA was associated with reduced DDAH activity.
  • Homocysteine-induced ADMA accumulation led to decreased nitric oxide synthesis.
  • Pyrrolidine dithiocarbamate partially reversed these effects.
  • Homocysteine directly inhibited recombinant human DDAH activity.

Conclusions:

  • Homocysteine post-translationally inhibits DDAH enzyme activity.
  • This inhibition causes ADMA accumulation, which in turn inhibits nitric oxide synthesis.
  • The study provides a molecular mechanism for homocysteine's adverse effects on endothelium-mediated vasodilation.
Abstract

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