Platelet-derived PCSK9 is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease

Abstract

Modern civilization’s sedentary lifestyle has found in CAD an increasing worldwide trend towards morbidity and mortality. Its incidence continues to peak as its risk factors, including hyperlipidemia, have also risen. Recently, a new component in cholesterol metabolism was identified. PCSK 9 proprotein convertase is expressed in many tissues and cell types, and binds to the LDL receptor, reducing the uptake of LDL-cholesterol particles from the extracellular compartment. PCSK9 has a major impact on lipoprotein homeostasis. Inhibition of PCSK9 results in lowered LDL and has shown improved prognosis in patients with coronary artery disease. Recent reports have highlighted additional effects of PCKS9, as a platelet activator and modulator of macrophage function and vascular inflammation. In this study, we characterized the release of PCSK9 from platelets and its consequences for thrombo-inflammation. We observed that platelet PCSK9 may contribute to atherothrombosis in a collective of CAD patients. This could be through a direct vascular effect, leading to increased aggregation, recruitment of leukocytes, and differentiation into foam cells; as well as indirectly through inhibition of LDL-receptor recycling and increase of plasmatic LDL, which in turn could increase platelet number and facilitate activation, creating a vicious cycle. Hence, it is tempting to assume that the herein-described effects of platelet PCSK9 on thrombosis and thrombo-inflammation might contribute to atherothrombosis. To summarize, platelets are potential additional and unexpected source of PCKS9 with potential impact on lipoprotein metabolism and further suggest PCSK9 as a thrombo-inflammatory promoter in coronary artery disease. In consequence, PCSK9 should be highlighted as a target in the treatment of vascular inflammation and hypercholesterolemia.