Non-Lipid Effects of PCSK9 Monoclonal Antibodies on Vessel Wall

Abstract

Elevated low density lipoprotein (LDL) cholesterol and lipoprotein(a) (Lp(a)) levels have an important role in the development and progression of atherosclerosis, followed by cardiovascular events. Besides statins and other lipid-modifying drugs, PCSK9 monoclonal antibodies are known to reduce hyperlipidemia. PCSK9 monoclonal antibodies decrease LDL cholesterol levels through inducing the upregulation of the LDL receptors and moderately decrease Lp(a) levels. In addition, PCSK9 monoclonal antibodies have shown non-lipid effects. PCSK9 monoclonal antibodies reduce platelet aggregation and activation, and increase platelet responsiveness to acetylsalicylic acid. Evolocumab as well as alirocumab decrease an incidence of venous thromboembolism, which is associated with the decrease of Lp(a) values. Besides interweaving in haemostasis, PCSK9 monoclonal antibodies play an important role in reducing the inflammation and improving the endothelial function. The aim of this review is to present the mechanisms of PCSK9 monoclonal antibodies on the aforementioned risk factors.

Keywords: PCSK9 monoclonal antibodies; coagulation; endothelial dysfunction; fibrinolysis; haemostasis; inflammation; thrombosis.

Figure 1

The role of PCSK9 in inflammation process. PCSK9 induces the expression of VEGF-A and ICAM-1 and, consequently, activates endothelial cells and stimulates monocyte/macrophage migration. The cascade promotes an inflammatory state and the progression of the atherosclerotic process. On the other hand, anti-inflammatory cytokines such as IL-10 attenuate the inflammatory response. PCSK9, proprotein convertase subtilisin/kexin type 9; VEGF-A, vascular endothelial growth factor A; ICAM-1, intracellular adhesion molecule-1; IL, interleukin; TNF-α, tumor necrosis factor-α.

Figure 2

The role of PCSK9 in platelets’ activity. High PCSK9 levels enhance platelet activation and reduce platelet responsiveness to acetylsalicylic acid, thus promoting atherosclerotic events. ASA, acetylsalicylic acid.

Figure 3

The role of PCSK9 in coagulation and fibrinolysis. PCSK9 induces the production of tissue factor, which is responsible for the activation of the extrinsic coagulation pathway and thrombus formation. TF, tissue factor; PAI-1, plasminogen activator inhibitor-1; F VIII, factor VIII.