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.

PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology

“…Targeting PCSK9 using monoclonal antibodies (mAbs) has emerged as an additional and additive therapy to treat hyperlipidaemia due to its regulation of LDLR [28][29][30][31]. However, several recent studies highlighted that PCSK9 can also have various additional effects that are independent of the LDLR, that provide more information on the involvement of PCSK9 in cancer, type 2 diabetes, obesity and several cardiovascular disorders [32][33][34].…”

Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and Atherosclerosis in ApoE−/− Mice

“…PCSK9 is a regulatory protein of lipid metabolism that was discovered by Seidah et al in 2003 (31). Its pathogenesis in atherosclerosis and application of inhibitors have been widely studied in recent years (14). Most studies of PCSK9 focused on hepatocytes, promoting LDLR degradation in lysosomes by binding with LDLR, thus increasing plasma LDL-C level.…”

“…In recent years, PCSK9 has attracted much attention in the field of lipid-lowering because of the powerful reduction of plasma LDL-C levels, amelioration of main adverse cardiovascular events and effect on stabilizing plaques with its inhibition (12,13). In addition to promoting the lysosomal degradation of LDL receptor LDLR on the surface of hepatocytes (14), PCSK9 can also act directly on blood vessel walls, by disrupting lipid intake and efflux of macrophages, promoting the secretion of inflammatory factors and inducing apoptosis to participate in atherosclerosis and even plaque destabilization (15,16). Ding et al (17) found that silencing PCSK9 in THP-1 macrophages could inhibit the formation of foam cells by downregulating the scavenger receptor CD36.…”

Successful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands

“…Interaction with the LDLR protein targets LDLR for degradation by the lysosomes and thereby prevents recirculation of LDLR to the cell membrane. To date,~30 GOF variants and another~30 LOF variants are known to be functional, and they are spread over the whole gene [42]. In the Netherlands, those PCSK9 GOF variants were detected in~5% of FH patients, compared to~20% APOB variants and 75% LDLR variants.…”

“…Similarly, in 2017, the variant Gln38Lys in APOC3 has been reported as a possible GOF variant causing hypertriglyceridemia, instead of the well-known LOF mechanisms leading to hypolipoproteinemia [41]. In addition, LOF variants in APOB can cause both hypercholesterolemia or hypobetalipoproteinemia, depending on the type and location of the variant in the gene; missense variants in exon 26 of APOB or nonsense variants in exon 29 lead to hypercholesterolemia, whereas nonsense variants in the first half of APOB cause hypobetalipoproteinemia [42,43]. APOB is a large gene containing many missense variants.…”