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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.
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.
Abstract:
High cholesterol levels are a known risk factor for coronary events. The molecular links between high serum cholesterol and the increased thrombogenicity of the arterial wall are still matter of investigation. In the present study we investigate the relationship between plasma cholesterol, thrombus formation and TF expression in a atherosclerotic rabbit model. Hypercholesterolemic rabbits showed a pronounced TF staining as well as NF-kappaB activation in the aortic arch. A consistent vessel wall platelet deposition was also observed. Treatment with fluvastatin reduced lipid accumulation, TF overexpression (-60%), NF-kappaB activation, and platelet deposition (-56%). In vitro studies showed that the drug upregulated IkappaB alpha in unstimulated as well as in TNFalpha-stimulated cells and also impaired the TNFalpha-induced Cdc42 prenylation, indicating that fluvastatin interferes with the transcriptional activation of TF gene. These results indicate that the prothrombotic phenotype of arterial wall, associated with elevated serum cholesterol levels, is mediated by TF overexpression. Fluvastatin treatment reduces the prothrombotic tendency by inhibiting TF synthesis.