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The role of hyperhomocysteinemia in nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-mediated

S G Heil1, A S De Vriese, L A J Kluijtmans

  • 1Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. s.heil@cukz.umcn.nl

Cellular and Molecular Biology (Noisy-Le-Grand, France)
|February 11, 2005
PubMed

Insights

Hyperhomocysteinemia impairs blood vessel function by affecting nitric oxide and EDHF pathways. Elevated S-adenosylhomocysteine levels in hyperhomocysteinemia may downregulate Connexin 40, disrupting vasodilation.

Area of Science:

  • Cardiovascular Biology
  • Endothelial Function
  • Metabolic Disorders

Background:

  • Hyperhomocysteinemia (HHcy) is linked to endothelial dysfunction, atherosclerosis, and thrombosis.
  • Impaired endothelial-dependent vasodilation is a key feature of HHcy.
  • Previous research suggests a role for nitric oxide (NO) pathway dysfunction in HHcy.

Purpose of the Study:

  • To investigate the impact of HHcy on endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation.
  • To explore the role of S-adenosylhomocysteine (AdoHcy) and Connexin 40 (Cx40) in HHcy-induced endothelial dysfunction.

Main Methods:

  • Analysis of endothelial nitric oxide synthase (eNOS) gene polymorphism in relation to venous thrombosis.
  • Diet-induced hyperhomocysteinemia in rats to study renal artery vasodilation.
  • Administration of S-adenosylhomocysteine hydrolase inhibitor (Adox).
  • Measurement of plasma total homocysteine (tHcy), kidney S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) levels.
  • Assessment of Connexin 40 (Cx40) mRNA expression in endothelial cells.

Main Results:

  • An eNOS gene variant (894 G>T) increased thrombosis risk in individuals with elevated homocysteine, suggesting impaired NO-mediated vasodilation.
  • Diet-induced HHcy in rats impaired EDHF-mediated renal artery vasodilation.
  • Adox treatment normalized plasma tHcy but did not prevent EDHF pathway inhibition.
  • Kidney AdoHcy and AdoMet levels increased in HHcy rats, decreasing the AdoMet:AdoHcy ratio.
  • Cx40 mRNA expression was downregulated in HHcy rats' endothelial cells, correlating with elevated kidney AdoHcy.

Conclusions:

  • HHcy-associated endothelial dysfunction involves impaired EDHF-mediated vasodilation.
  • Elevated AdoHcy levels in HHcy may lead to decreased Cx40 expression.
  • These molecular changes contribute to impaired vasodilation in HHcy.

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