PCSK9 Biology and Its Role in Atherothrombosis

Abstract

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.

Keywords: atherosclerosis; hypercholesterolemia; low-density lipoprotein; low-density lipoprotein receptor; platelets; proprotein convertase subtilisin/kexin type 9; thrombosis.

Figure 1

Processing of the zymogen pre-proPCSK9 leading to the cleaved PCSK9 mature form. SP: signal peptide.

Figure 2

PCSK9 effects on targeting low-density lipoprotein receptor (LDLR) towards lysosomal degradation or recycling, depending on PCSK9 binding to cyclase-associated protein 1 (CAP-1). In the absence of PCSK9 (A), the LDLR-LDL complex is internalized into endosomes through a clathrin-dependent mechanism and LDLR is recycled to the cell surface. In the presence of PCSK9, the LDLR-LDL complex is internalized into endosomes through a clathrin-dependent mechanism (B) and LDLR is recycled to the cell surface if CAP-1 binding to PCSK9 does not occur. Instead, LDLR undergoes caveolae-dependent endocytosis (C) and lysosomal degradation if CAP-1 binds PCSK9. To inhibit PCSK9 action, two approved types of drugs, which are antibody based, act through targeting the extracellular PCSK9 (alirocumab, evolocumab), or through the small interfering RNA, targeting the intracellular synthesis of PCSK9 (inclisiran).

Figure 3

Effects of the main natural mutations of the PCSK9 domains on cholesterol homeostasis phenotype and their impact on cardiovascular disease risk. LOF: loss-of-function; GOF: gain-of-function; LDL: low-density lipoprotein; LDLR: LDL receptor; LDL-C: LDL cholesterol; CV: cardiovascular; CHR: cysteine- and histidine-rich domain.

Figure 4

Molecular pathways implicated in the PCSK9 effects on endothelial cells, macrophages and platelets, leading to atherothrombosis. LDL: low-density lipoprotein; oxLDL: oxidized LDL; LOX-1: lectin-like oxidized low-density lipoprotein receptor 1; SRA: scavenger receptor A; CD36: cluster of differentiation 36; NLRP3: NOD-like receptor pyrine domain-containing protein 3; PLA₂: phospholipase A₂; AA: arachidonic acid; COX: cyclooxygenase; TX: thromboxane; GPIIb/IIIa: glycoprotein IIb/IIIa.

Figure 5

Treatment algorithm to pharmacologically decrease low-density lipoprotein cholesterol (LDL-C) levels in patients with acute coronary syndrome (ACS) according to the recent European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines.