Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Beyond Lipids: The Role in Oxidative Stress and Thrombosis

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors' degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.

Keywords: anti-PCSK9; oxidative stress; platelets; proprotein convertase subtilisin/kexin type 9 (PCSK9); thrombosis.

Figure 1

PCSK9 effects on platelet activation. (1) PCSK9 directly binds CD36 receptor on platelet’s surface, enhancing platelet activation and the downstream signaling, including (2) Src and (3) JNK kinase. Moreover, PCSK9 increases the generation of ROS by (4) p38MAPK phosphorylation inducing (5) Nox2 activation, (6) PLA2, (7) AA and (8) TxA2 signaling. (9) The Nox2-mediated ROS production increases (10) ox-LDLs formation that amplify the platelet activation through both (11a) LOX1 and (11b) CD36 platelet receptors. All these events act as the amplifying signal for platelet activation leading to (12) p-selectin expression, (13) CD40L expression and (14) release of granule contents. (15) mAbs-PCSK9 inhibit all these mechanisms. Abbreviations. AA: arachidonic acid; CD40L: CD40 ligand; Gp: glycoprotein; H₂O₂: hydrogen peroxide; JNK: c-Jun N-terminal kinase; LDL: low-density lipoproteins; MAPK: mitogen-activated protein kinase; ox-LDLs: oxidized low-density lipoproteins; PCSK9: proprotein convertase subtilisin/kexin 9; PLA2: phospholipase A2; ROS: reactive oxygen species; sNOX2-dp: soluble NOX2-derived peptide; TP: thromboxane receptor; TxA2: thromboxane A2; LOX-1: Lectin-like ox-LDL receptor-1; mAbs: monoclonal antibodies.