Platelet-Derived PCSK9 Is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease

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.

PCSK9 Promotes Cardiovascular Diseases: Recent Evidence about Its Association with Platelet Activation-Induced Myocardial Infarction

“…Accordingly, collective studies have demonstrated that PCSK9 directly promotes atherosclerosis by being involved in atherosclerotic inflammation [16][17][18]. Furthermore, recent studies suggested a novel role for PCSK9 in promoting atherosclerosis through platelet activation, a key role during atherogenesis and in atherothrombosis-induced MI [35,36,[62][63][64]. Notably, several clinical studies have demonstrated the antiplatelet effects of PCSK9 in patients with hypercholesterolemia and found it to be an effective and safe strategy for treating patients with uncontrolled hyperlipidemia and coronary artery disease [65,66].…”

“…Another interesting in vitro study was conducted by Petersen et al, who demonstrated that PCSK9 was stored and released by platelets in the presence of LDL [64]. The PCSK9-derived platelet was found to promote platelet aggregation, thrombus formation, monocyte migration, and monocyte differentiation into foam cells, all of which contributed to the occurrence of atherosclerosis progression-induced coronary artery disease [64]. Next, experimental studies were performed in an attempt to find a potential mechanism underlying PCSK9 and platelet activation in the progression of atherosclerosis.…”

Pleiotropic Effects of PCSK9: Focus on Thrombosis and Haemostasis

“…Furthermore, it has recently been described for the first time that platelets also express PCSK9 upon activation in the presence of LDL, and that its secretion by platelets further contributes to their aggregation and thrombus formation. In addition, this promotes monocyte differentiation into macrophages/foam cells, also contributing to atherogenesis [ 65 ].…”

“…The effect of PCSK9 inhibitors on platelet function has been extensively studied. Monoclonal antibodies against PCSK9 reduce platelet activation and platelet–dependent immunothrombosis [ 65 , 90 ]. Inclisiran, a small interfering RNA-based PSCK9, has not shown any effect on platelets thus far [ 91 ].…”

Non-Lipid Effects of PCSK9 Monoclonal Antibodies on Vessel Wall

“…In the presence of PCSK9 antibodies platelet aggregation was significantly attenuated. As a result, in presence of PSCK9 antibodies, platelet-dependent thrombus formations significantly reduced [68]. Many studies indicate that statins [69] and PCSK9 monoclonal antibodies [70] have an effect on the hemostatic system.…”