Dyslipidemia and the oxidative stress associated with it are among the main risk factors leading to atherothrombosis. Platelet activation plays a key role in atherothrombosis and the subsequent acute coronary syndromes triggered by plaque rupture. Many dyslipidemia- related pathophysiological states are associated with a drastically increased response of platelets to agonists. While the significance of increased platelet reactivity in the pathophysiology of occlusive arterial thrombosis is widely recognized, knowledge of molecular mechanisms leading to enhanced platelet reactivity in vivo during hyperlipidemia has only started to emerge. Involvement of platelet pattern recognition receptors in platelet function has been recently appreciated. We have previously demonstrated that the platelet scavenger receptor CD36 serves as the platelet sensor for oxidative stress and promotes platelet hyperreactivity in dyslipidemia. Recently, we and others have demonstrated that TLRs, another family of pattern recognition receptors with previously unknown role in platelets, can regulate platelet function. Our recent data demonstrate that platelet TLR1/TLR2 and TLR9, alone or in collaboration with CD36, recognize novel altered-self ligands that accumulate in the circulation during oxidative stress and dyslipidemia. Ligation of these receptors activates pathways common to the innate immunity system, and connects this signaling to the integrin activation network in platelets via links that have not yet been established. Generation of biologically-active oxidized lipids and related products is a critical consequence of oxidative stress. According to our studies these molecules represent altered self ligands for platelet pattern recognition receptors. We have previously identified a novel family of oxidized choline glycerophospholipids (oxPCCD36) that serve as high affinity ligands for CD36 and promote platelet hyperreactivity and thrombosis in vivo via CD36. Our recent studies extended this observation to a novel class of products formed via degradation of oxPCCD36 by PLA2. We showed that carboxyalkylpyrrole adducts of proteins and phosphatidylethanolamine are novel ligands for platelet TLRs, are powerful platelet agonists and accumulate in vivo in dyslipidemia. However, the exact molecular mechanisms of receptor recognition, the contribution to thrombosis in vivo of novel ligands and the signaling pathways they induce in platelets are not known. This proposal will address the hypothesis that platelet TLRs, alone or in cooperation with CD36, promote platelet reactivity and the prothrombotic state induced by endogenous ligands generated during oxidative stress.
The likelihood of thrombosis is increased in dyslipidemia. An important contributing factor is heightened platelet reactivity, i.e., a drastically increased response of platelets to agonists. We are identifying novel molecules accumulating in circulation in dyslipidemia that can promote platelet reactivity via a set of receptors that was not previously associated with platelet function. Interaction of these receptors with novel ligands activates pathways common to the innate immunity system, and connects this signaling to the platelet activation network eventually leading to accelerated thrombosis. Our studies of these pathways will allow the identification of new approaches preventing thrombosis in dyslipidemia.
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