Abstract 19091: Platelet mTOR is an Important Mediator of Arterial Thrombosis
Background: Arterial thrombosis is responsible for peripheral vascular disease, ischemic stroke, and myocardial infarction. Mammalian target of rapamycin (mTOR) inhibition promotes arterial thrombosis. To determine the contributions of platelet specific mTOR deficiency to arterial thrombosis, we generated platelet specific mTOR deficient mice. To determine the rescue effect of platelet mTOR deficiency, we also generated platelet specific TSC1 deficient (PF4Cre-TSC1flox/flox) mice. Because the effect of mTOR activation on thrombus formation in vivo has not yet been studied, we hypothesize that mTOR signaling pathway in platelets may play an important role in arterial thrombosis.
Methods and Results: To determine the role of platelet mTOR in arterial thrombosis, we generated a mouse strain with platelet-specific mTOR deficiency (PF4Cre-mTORflox/flox) using conditional mTORflox/flox mice and platelet-specific PF4Cre mice. PF4Cre-mTORflox/flox mice did not show any obvious phenotypic abnormalities. Arterial thrombus formation was investigated using in vivo ferric chloride induced thrombosis model. Ferric Chloride (5% FeCl3) induced thrombotic occlusion. Rapamycin treatment and mTOR conditional knockout induced arterial thrombosis significantly. Compared to PF4Cre mice, PF4Cre-TSC1flox/flox mice exhibited elongated thrombotic occlusion time by 51.7%. Platelet specific mTOR deficiency induced arterial thrombosis quickly compare to the WT via activation of p-S6, a downstream target of mTORC1 and inhibition of p-Rictor of mTORC2.
Conclusion: These finding indicate that platelet specific mTOR deficiency resulted in significantly induced arterial thrombosis but delayed at the platelet specific TSC1 deficient mice. These results suggest that activation of mTORC1 may have therapeutic benefits in arterial thrombosis.
- © 2013 by American Heart Association, Inc.