Die Rolle der Thrombozyten- und Leukozyten-Endothelzell-Interaktion in der Atherogenese

The role of thrombocyte- and leukocyte-endothelial cell-interaction
in atherogenesis - an in vivo-study in the ApoE-knock-out-mouse -
Platelets play a crucial role in thromboembolic complications of
advanced atherosclerotic lesions but their involvement in the
initiation of the atherosclerotic process in unclear. Platelet
adhesion regulates secretion of intracellulary stored
proinflammatory and proliferative mediators. In vitro, platelets
promote the expression of inflammatory genes in endothelial cells,
including adhesion receptors and chemokines suggesting a
proatherogenic role of platelets. Here, we show in vivo that
platelets adhere to the vascular endothelium of the carotid artery
in ApoE-deficient mice prior to the development of manifest
atherosclerotic lesions. Glycoprotein (GP-)Ib and GPIIb-IIIa are
the predominant adhesion receptors mediating platelet adhesion to
the endothelium of the carotid artery and may play a crucial role
in the genesis of platelet-mediated atherosclerosis. In this
experiments we could demonstrate the crucial role of these two
receptors for platelet adhesion. While anti-GPIb reduced transient
adhesion for 85% and permanent adhesion for 99%, anti-GPIIb-IIIa
shows a 95%-reduction of permanent adherent platelets. Long–term
antibody-treatment (anti-GPIb) shows by a substantial reduction of
plaque area from 60% in the aorta and 81% in the carotid arterya a
crucial influence of atheroprogression. Together, prolonged
inhibition of platelet adhesion (with anti-GPIb) in ApoE-deficient
mice profoundly inhibited arterisclerotic lesion formation. These
findings establish platelets as major players in initiation of the
atherogenic process and may have important implications for the
development of novel anti-atherosclerotic therapies.