Sample Issue of Trigger

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TRIGGER

The Twice-monthly Electronic Newsletter on the
Biology of Tissue Factor, Factor VII and TFPI

Vol. 8, No.5      March 1, 2002

(The next issue will be e-mailed on March 15, 2002)
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PAPERS IN PRESS

AUTHORS: Baetta R, Camera M, Comparato C, Altana C, Ezekowitz MD and
Tremoli E.
TITLE: Fluvastatin Reduces TF Expression and Macrophage
Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the
Absence of Lipid Lowering.
JOURNAL: Arteriosclerosis, Thrombosis and Vascular Biology
ABSTRACT: The expression of TF, mainly by infiltrated inflammatory
cells, has been shown to be responsible for the thrombogenicity
associated with atheroma. The contribution of the nonlipid-related
effects of statins to the clinical benefits of statin therapy is
currently under intense investigation. In this study we evaluated
the ability of fluvastatin to modulate TF expression and macrophage
accumulation in rabbit carotid intimal lesions, independently of
cholesterol lowering.
Male rabbits were fed for 30 days a 1% cholesterol-rich diet
with (HC+F) or without (HC) 5 mg/kg/day fluvastatin. Two weeks from
the start of treatments a silastic collar was placed around the
carotid artery. Fifteen days later animals were killed and carotid
segments were excised and processed. Atherogenic diet caused a
consistent increase in plasma cholesterol levels (610 ± 231 mg/dl
vs. 50 ± 9 at baseline), which were not affected by fluvastatin (603
± 248). In HC rabbits, an intimal lesion with macrophage
accumulation and TF expression was detected. Fluvastatin
significantly reduced TF and macrophage content of the lesion (-50%
for both). Results indicate that fluvastatin may attenuate the
inflammatory and thrombogenic potential of atherosclerotic lesions
through mechanism(s) other than cholesterol reduction, providing new
insight regarding the complex mode of action of statins.
SUBMITTED BY: Marina Camera

* * * * *

AUTHORS: Camera M, Toschi V, Comparato C, Baetta R, Rossi F,
Fuortes M, Ezekowitz MD, Paoletti R, Tremoli E.
TITLE: Cholesterol-Induced Thrombogenicity of the Vessel Wall:
Inhibitory Effect of Fluvastatin
JOURNAL: Thrombosis and Haemostasis
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 a
matter of investigation. In the present study we investigate the
relationship between plasma cholesterol, thrombus formation and TF
expression in an atherosclerotic rabbit model.
Hypercholesterolemic rabbits showed a pronounced TF staining
as well as NF-kB activation in the aortic arch. A consistent vessel
wall platelet deposition was also observed. Treatment with
fluvastatin reduced lipid accumulation, TF overexpression (-60%),
NF-kB activation, and platelet deposition (-56%). In vitro studies
showed that the drug upregulated IkBa in unstimulated as well as in
TNF{alpha}-stimulated cells and also impaired the TNF{alpha}-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.
SUBMITTED BY: Marina Camera
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UPCOMING MEETINGS & EVENTS

The Sixteenth Symposium of the Protein Society will take place
August 17-21, 2002 at the San Diego Marriott Hotel and Marina, San
Diego, California. The deadline for abstracts is Wednesday, April
3. For more information, go to:
http://www.faseb.org/meetings/protein02
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POSITIONS SOUGHT/AVAILABLE

PhD Studentship available:

A three year Ph.D. research studentship investigating "the role
of tissue factor..." (NOTE: we have deleted the rest of this
announcement as it has expired.)
For informal enquires and information regarding the project
please contact Dr xxxxxxxxx

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RECENT PUBLICATIONS ON TISSUE FACTOR, FACTOR VII, AND TFPI
(Culled from Reference Update Deluxe Edition by searching
titles and keywords; search may not be exhaustive)

Adcock DM and Johnston M (2002) Evaluation of frozen plasma
calibrants for enhanced standardization of the international
normalized ratio (INR): A multi-center study. Thromb Haemost
87:74-79.

Asakura H, Suga Y, Aoshima K, Ontachi Y, Mizutani T, et al. (2002)
Marked difference in pathophysiology between tissue factor- and
lipopolysaccharide-induced disseminated intravascular coagulation
models in rats. Crit Care Med 30:161-164.

Butenas S, Brummel KE, Branda RF, Paradis SG, and Mann KG (2002)
Mechanism of factor VIIa-dependent coagulation in hemophilia blood.
Blood 99:923-930.

De Cristofaro R, Rocca B, Marchioli R, and Landolfi R (2002) Plasma
protein oxidation is associated with an increase of procoagulant
markers causing an imbalance between pro- and anticoagulant pathways
in healthy subjects. Thromb Haemost 87:58-67.

Eigenbrot C and Kirchhofer D (2002) New insight into how tissue
factor allosterically regulates Factor VIIa. Trends Cardiovasc Med
12:19-26.

Horie S, Hiraishi S, Hamuro T, Kamikubo Y, and Matsuda J (2002)
Oxidized low-density lipoprotein associates strongly with
carboxy-terminal domain of tissue factor pathway inhibitor and
reduces the catalytic activity of the protein. Thromb Haemost
87:80-85.

Konduri SD, Osman FA, Rao CN, Srinivas H, Yanamandra N, et al.
(2002) Minimal and inducible regulation of tissue factor pathway
inhibitor-2 in human gliomas. Oncogene 21:921-928.

Ng TMH, Cheang KI, Munger MA, and Callahan KS (2002) Neurohormonal
activation does not explain elevated tissue factor expression in
heart failure. Thromb Haemost 87:176-177.

Ott I, Malcouvier V, Schömig A, and Neumann FJ (2002) Proteolysis of
tissue factor pathway inhibitor-1 by thrombolysis in acute
myocardial infarction. Circulation 105:279-281.

Örning L, Fischer PM, Hu CK, Agner E, Engebretsen M, Husbyn M,
Petersen LB, Orvim U, Llinas M, and Sakariassen KS (2002) A cyclic
pentapeptide derived from the second EGF-like domain of factor VII
is an inhibitor of tissue factor dependent coagulation and thrombus
formation. Thromb Haemost 87:13-21.

Pendurthi UR, Meng F, Mackman N, and Rao LVM (2002) Mechanism of
resveratrol-mediated suppression of tissue factor gene expression.
Thromb Haemost 87:155-162.

Poller L, Keown M, Chauhan N, Van den Besselaar AMHP,
Meeuwisse-Braun J, Tripodi A, Clerici M, and Jespersen J (2002)
European concerted action on anticoagulation. Use of plasma samples
to derive international sensitivity index for whole-blood
prothrombin time monitors. Clin Chem 48:255-260.

Shah PK (2002) Reduced tissue factor pathway inhibitor-1 after
pharmacological thrombolysis - An epiphenomenon or potential culprit
in rethrombosis? Circulation 105:270-271.

Souto JC, Almasy L, Borrell M, Stone WH, Blanco-Vaca F, Soria JM,
Blangero J, and Fontcuberta J (2002)
Thromboplastin-thrombomodulin-mediated time and serum folate levels
are genetically correlated with the risk of thromboembolic disease:
Results from the GAIT project. Thromb Haemost 87:68-73.

Van Rooijen M, Von Schoultz B, Silveira A, Hamsten A, and Bremme K
(2002) Different effects of oral contraceptives containing
levonorgestrel or desogestrel on plasma lipoproteins and coagulation
factor VII. Am J Obstet Gynecol 186:44-48.

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