Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin.
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.
Camera
Marina
M
Department of Pharmacological Sciences, University of Milan, Italy.
Toschi
Vincenzo
V
Comparato
Carmen
C
Baetta
Roberta
R
Rossi
Francesca
F
Fuortes
Michele
M
Ezekowitz
Michael D
MD
Paoletti
Rodolfo
R
Tremoli
Elena
E
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000925:Anticoagulants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017984:Enoxaparin / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D000077340:Fluvastatin; D005786:Gene Expression Regulation / Q000187:drug effects*; D018056:Hemorheology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D020672:I-kappa B Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010973:Platelet Adhesiveness; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D019851:Thrombophilia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D000924:Anticholesteremic Agents; D000925:Anticoagulants; D017984:Enoxaparin; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D007211:Indoles; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000077340:Fluvastatin; D013925:Thromboplastin; D002784:Cholesterol; D020764:cdc42 GTP-Binding Protein