Abstract 11886: Targeting the PGE2/EP3 Pathway Differentiated Thrombosis From Hemostasis in Mice
Hemostasis interrupts bleeding from disrupted blood vessels by activating platelet aggregation and coagulation. If uncontrolled, this process generates obstructive thrombi and the resulting endoluminal clot is termed thrombosis or atherothrombosis when occurring on atherosclerotic plaques. Whether some molecular mechanisms differentiate controlled hemostasis from pathological thrombosis is not clear. We hypothesized here that the prostaglandin PGE2 activating its platelet receptor EP3 might play such a role in mice. First, we confirmed that EP3 gene deletion does not increase mouse bleeding from tail (307±31 µl, n=15 Ep3+/+ mice versus 364±32 µl, n=18 Ep3-/- mice, P>0.05). We observed similar differences when investigating tail, liver or cerebral bleeding in mice receiving DG-041, a specific blocker for EP3. Then we showed that blockade of EP3 with DG-041 prevented thrombosis on arachidonic acid- and ferric chloride- induced mouse models of arterial thrombosis. In addition, DG-041 drastically inhibited atherothrombosis provoked by scratch-induced rupture of carotid atherosclerotic plaques, as quantified by videomicroscopy (0.02±0.01 × 105 pixels/min, n=12 versus controls 1.80±0.60 × 105 pixels/min, n=13, P=0.0047). We finally showed that thrombosis prevention with clopidogrel on the ferric chloride model was significantly improved by adjunction of DG-041 60 mg/Kg (thrombosis extent dropped from 10.72±2.46 × 105 pixels/min, n=14 to 3.12±1.13 × 105 pixels/min, n=13, P<0.05). By contrast, associating DG-041 60mg/Kg to clopidogrel 2.5 mg/Kg did not increase the tail bleeding times (282±51s, n=14, P>0.05 vs clopidogrel 242±49s, n=15, P>0.05) more than did clopidogrel alone (controls: 130±10 sec, n=9; P>0.05 vs. clopidogrel alone). We concluded that it is possible to dissociate thrombosis from hemostasis by targeting the PGE2/EP3 pathway in mice.
- © 2011 by American Heart Association, Inc.