Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

Abstract

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating low-density lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.

Keywords: Atherosclerosis; Inflammation; LDL-C; Mitochondrial DNA; PCSK9.

Fig. 1

PCSK9 in lipid metabolism. a (1) The canonical pathway: secreted PCSK9 can bind to the EGF-A domain of low-density lipoprotein receptor (LDLR) on the cell surface and be internalized with LDLRs in endocytic vesicles. The PCSK9–LDLR complex is then degraded in lysosomes. (2) Intracellular endogenous PCSK9-induced LDLR degradation: PCSK9 can bind to LDLR in the luminal secretory compartment and target LDLR to lysosomes in vesicles emanating from the trans-Golgi. (3) PCSK9-mediated very low-density lipoprotein receptor (VLDLR) degradation: the EGF-A domain of VLDLR is homologous to the EGF-A domain of LDLR. Extracellular PCSK9 interacts with VLDLR by binding with the EGF-A domain to form an endocytosed complex that is degraded in lysosomes. b The Beclin-1/ATG14L complex initiates the autophagy process that degrades apolipoprotein B (apoB). P62 shuttles proteins and organelles to autophagosomes for degradation. The conversion of LC3-I to LC3-II indicates active turnover of the autophagy process. PCSK9 interacts with apoB, resulting in the inhibition of the degradation pathway of apoB via this autophagic mechanism. Thus, the secretion of apoB100, as the particles VLDL, LDL, and Lipoprotein(a) (Lp(a)), into circulation is increased. PCSK9 antibodies increase the expression of LDLR, which can bind with exogenous Lp(a). Thus, the Lp(a)/LDLR complex is internalized and undergoes the lysosome degradation pathway

Fig. 2

PCSK9-regulated expression of inflammatory cytokines and scavenger receptors. NF-κB is bound to IκBα in the cytoplasm in the resting state. With cell stimulation, such as with oxidized-LDL (ox-LDL), IκBα is degraded and the released NF-κB is then translocated into the nucleus to activate the transcription of target genes including inflammatory cytokines. In ox-LDL-induced macrophagocytes, PCSK9 enhances the expression of TLR4, which can promote NF-κB nuclear translocation. Then, the expression and secretion of inflammatory factors, including IL-1, IL-6, monocyte chemo-attractant protein 1 (MCP-1), and TNF-α, are increased. a PCSK9 promotes the expression of different scavenger receptors (SRs), including SR-A, CD36, and LOX-1 in macrophagocytes, thus enhancing ox-LDL uptake in macrophagocytes. b PCSK9 promotes expression of different SRs, including SR-A, CD36, and LOX-1 in macrophagocytes, thus enhancing ox-LDL uptake in macrophagocytes

Fig. 3

PCSK9-regulated migratory capacity of monocytes. PCSK9 decreases the LDLR on the cell surface of a monocyte. As a result, the accumulated circulating low-density lipoprotein-cholesterol (LDL-C) stimulates the expression of C–C chemokine receptor 2 (CCR2), which serves as the receptor of MCP-1. Thus, the monocyte can migrate towards MCP-1 and accumulate in the arterial wall