Download Regulation of Tissue Factor Expression

Regulation of Tissue Factor Expression
Implications for Coronary Artery Disease
By Giovanni G. Camici, Institute of Physiology University of Fribourg, Switzerland.
Risk factors such as diabetes, hypertension, obesity and smoking can disturb the integrity of
the endothelium rendering it dysfunctional. A dysfunctional endothelium facilitates the entry
and oxidation of circulating lipoproteins and monocytes leading to atherosclerotic plaque
formation. Rupture of unstable plaques is responsible for coronary thrombosis, the main
cause of unstable angina, acute myocardial infarction, and sudden cardiac death.
Percutaneous transluminal coronary angioplasty (PTCA) is a clinical procedure routinely
employed to revascularise occluded vessels. Following PTCA a tube-like metal structure
coated with antiproliferative drugs, a stent, is inserted into the vessel to prevent it from
occluding once again. Unlike for restenosis, recent evidence has shown that the incidence of
in stent thrombosis has not decreased following the advent of drug eluting stents. Rapamycin
which is widely used for coating stents has been shown to induce the expression of TF, the
key initiator of the coagulation cascade. In the first part of this thesis we characterised the
impact of paclitaxel, the main alternative to rapamycin, on TF expression in human
endothelial cells. Indeed, paclitaxel enhanced endothelial TF protein expression and activity
through the specific activation of JNK. This observation provides novel insights into the
pathogenesis of thrombus formation after paclitaxel-eluting stent deployment.
In the second part of the thesis we directed our efforts at characterising the potential
application of Dimethyl sulfoxide (DMSO) as a novel agent to be used for stent coating.
DMSO is used for preservation of hematopoietic progenitor cells and infused into patients
undergoing bone marrow transplantation. Despite of its intravenous application, the impact of
DMSO on vascular cells has not been assessed. We found that DMSO inhibits TF expression
in human endothelial cells, monocytes, and VSMC. This effect was mediated by reduced
activation of the MAP kinases JNK and p38. In vivo, DMSO treatment suppressed TF activity
and prevented thrombotic occlusion in a mouse model of carotid artery photochemical injury.
DMSO also inhibited VSMC proliferation and migration; moreover, it prevented rapamycin and
paclitaxel-induced upregulation of TF expression. As the use of DMSO is established in
different areas of modern medicine, we propose this drug as a novel strategy for treating
acute coronary syndromes; in particular, DMSO seems to represent an attractive compound
for application on drug-eluting stents, either alone or in combination with rapamycin or
paclitaxel.
Members of the jury: Prof. Dr. Zhihong Yang, (Supervisor of the thesis), Prof. Dr. Daniel
Hayoz, Prof. Dr. Jean-Pierre Montani, Prof. Dr. Thomas F. Lüscher, Prof. Dr. Eric Rouiller,
President of the jury.