Abstract
Platelets play a significant role in atherothrombosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of LDL metabolism and interacts with platelet function. The effect of PCSK9 in platelet function is poorly understood. The authors of this article sought to characterize platelets as a major source of PCSK9 and PCSK9’s role in atherothrombosis. In a large cohort of patients with coronary artery disease (CAD), platelet count, platelet reactivity, and platelet-derived PCSK9 release were analyzed. The role of platelet PCSK9 on platelet and monocyte function was investigated in vitro. Platelet count and hyper-reactivity correlated with plasma LDL in CAD. The circulating platelets express on their surface and release substantial amounts of PCSK9. Release of PCSK9 augmented platelet-dependent thrombosis, monocyte migration, and differentiation into macrophages/foam cells. Platelets and PCSK9 accumulated in tissue derived from atherosclerotic carotid arteries in areas of macrophages. PCSK9 inhibition reduced platelet activation and platelet-dependent thrombo-inflammation. The authors identified platelets as a source of PCSK9 in CAD, which may have an impact on LDL metabolism. Furthermore, platelet-derived PCSK9 contributes to atherothrombosis, and inhibition of PCSK9 attenuates thrombo-inflammation, which may contribute to the reported beneficial clinical effects.
Highlights
Platelets are critical regulators of thrombosis and inflammation [1]
The major findings of the present study are the following. (i) Platelet count correlates with plasma-low-density lipoprotein (LDL) cholesterol. (ii) Platelets store and release Proprotein convertase subtilisin/kexin type 9 (PCSK9) upon actiwith plasma-LDL cholesterol. (ii) Platelets store and release PCSK9 upon vation, which is enhanced in the presence of LDL. (iii) PltPCSK9 promotes platelet aggreactivation, which is enhanced in the presence of LDL. (iii) PltPCSK9 promotes platelet gation andand thrombus formation under flowflow dynamic conditions
(vi) PltPCSK9 is found in substantial amounts in atherosclerotic tissue
Summary
Platelets are critical regulators of thrombosis and inflammation [1]. Platelets release prothrombotic (e.g., adenosine diphosphate (ADP)) or proinflammatory (e.g., cytokines or chemokines) compounds that promote endothelial activation and vascular lesions (thrombo-inflammation) [2]. Activated platelets augment vascular inflammation, resulting in atheroprogression [3]. Enhanced activity of circulating platelets is associated with an increase in cardiovascular events and death in patients with coronary artery disease [4]. Antiplatelet therapy is critical in preventing acute atherothrombotic events but does not control the progression of plaque and atherosclerotic disease. Hyperlipidemia is associated with increased coagulation and platelet activity [5]
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