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Interference in mevalonate pathway ameliorates homocysteine-induced endothelium-dysfunction

Biqi Zhang1, Lihong Qiu, Michael Fu

  • 1Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

European Journal of Pharmacology
|July 17, 2012
PubMed

Insights

Homocysteine damages blood vessels by affecting cholesterol and oxidative pathways. Targeting these pathways, particularly the mevalonate pathway, can protect endothelial function.

Area of Science:

  • Biochemistry
  • Cardiovascular Biology
  • Cellular Physiology

Background:

  • Homocysteine is a known risk factor for atherosclerosis and hypertension.
  • Endothelial dysfunction is a critical early event in these cardiovascular diseases.
  • Cholesterol accumulation and reactive oxygen species contribute significantly to endothelial damage.

Purpose of the Study:

  • To investigate the role of the mevalonate and oxidative pathways in homocysteine-induced endothelial damage.
  • To determine if interventions targeting these pathways can protect endothelial function.

Main Methods:

  • Isometric tension measurements in rat aortic rings to assess vasorelaxation.
  • Measurement of nitric oxide (NO) levels and NO synthase (NOS) activity in endothelial cells.
  • Assessment of superoxide anion and cholesterol accumulation.
  • Pharmacological interventions using simvastatin, squalestatin, superoxide dismutase, mevalonolactone, and squalene.

Main Results:

  • Homocysteine impaired endothelium-dependent vasorelaxation, reduced NO levels and NOS activity, and increased superoxide anion and cholesterol.
  • Asymmetric dimethylarginine levels were unaffected by homocysteine.
  • Squalestatin and superoxide dismutase partially exacerbated homocysteine's adverse effects.
  • Simvastatin completely ameliorated homocysteine-induced endothelial dysfunction.
  • Mevalonolactone and squalene modulated the effects of simvastatin and squalestatin, respectively.

Conclusions:

  • The mevalonate pathway, in addition to the oxidative pathway, mediates homocysteine-induced endothelial dysfunction.
  • Interfering with both the mevalonate and oxidative pathways offers effective protection against endothelial damage caused by homocysteine.

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