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Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin

Marina Camera1, Vincenzo Toschi, Carmen Comparato

  • 1Department of Pharmacological Sciences, University of Milan, Italy.

Thrombosis and Haemostasis
|May 15, 2002
PubMed

Insights

High cholesterol promotes arterial wall thrombogenicity via tissue factor (TF) overexpression. Fluvastatin treatment effectively reduced TF levels and platelet deposition in an atherosclerotic rabbit model, mitigating this prothrombotic risk.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Atherosclerosis Research

Background:

  • Elevated serum cholesterol is a significant risk factor for coronary events.
  • The precise molecular mechanisms linking hypercholesterolemia to arterial thrombogenicity remain under investigation.
  • Tissue Factor (TF) is implicated in the prothrombotic state associated with atherosclerosis.

Purpose of the Study:

  • To investigate the relationship between plasma cholesterol levels, thrombus formation, and TF expression in an atherosclerotic rabbit model.
  • To determine the effect of fluvastatin on TF expression and associated prothrombotic markers.
  • To elucidate the in vitro mechanisms by which fluvastatin may inhibit TF synthesis.

Main Methods:

  • Utilized a hypercholesterolemic rabbit model of atherosclerosis.
  • Quantified TF expression, NF-kappaB activation, and platelet deposition in aortic tissues.
  • Assessed the impact of fluvastatin treatment on lipid accumulation and prothrombotic markers.
  • Conducted in vitro studies to examine fluvastatin's effects on cellular signaling pathways related to TF gene transcription.

Main Results:

  • Hypercholesterolemic rabbits exhibited increased TF staining, NF-kappaB activation, and platelet deposition in the aortic arch.
  • Fluvastatin treatment significantly reduced lipid accumulation, TF overexpression (by 60%), NF-kappaB activation, and platelet deposition (by 56%).
  • In vitro, fluvastatin upregulated IkappaB alpha and impaired TNFalpha-induced Cdc42 prenylation, suggesting interference with TF gene transcriptional activation.

Conclusions:

  • Elevated serum cholesterol contributes to arterial wall prothrombotic phenotype through TF overexpression.
  • Fluvastatin effectively reduces the prothrombotic tendency associated with hypercholesterolemia by inhibiting TF synthesis.
  • These findings highlight TF as a key mediator in cholesterol-induced thrombogenicity and fluvastatin as a potential therapeutic agent.

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