Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke

Abstract

Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the proprotein convertase family. It is an important regulator of cholesterol metabolism. PCSK9 can bind to low-density lipoprotein receptors (LDLRs) and induce the degradation of these receptors through the endosome/lysosome pathway, thus decreasing the LDLR levels on the cell surface of hepatocytes, resulting in increased serum low-density lipoprotein cholesterol (LDL-C) concentrations. Recent studies have found that gene polymorphisms of PCSK9 are associated with hypercholesterolemia, risk of atherosclerosis, and ischemic stroke. Furthermore, monoclonal antibodies, peptide mimetics, small molecule inhibitors and gene silencing agents that are associated with PCSK9 are some of the newer pharmaceutical therapeutic strategies and approaches for lowering serum LDL-C levels. In this review, we will discuss recent advances in PCSK9 research, which show that PCSK9 is correlated with lipid metabolism, atherosclerosis, and, in particular, ischemic stroke. We will also discuss the current state of PCSK9 therapeutics and their potential in modulating these diseases.

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

“…This neutral effect on cognition has been recently reported by the EBBINGHAUS study, Drugs (even apparently specific monoclonal antibodies) can exert actions on more than one protein if such targets belong to a family of structurally similar proteins. PCSK9, for example, is one of nine related proprotein convertases (32). Such 'off-target' actions, whether beneficial or deleterious, would not be shared by variants in the gene encoding the target of interest.…”

The Influence of OLR1 and PCSK9 Gene Polymorphisms on Ischemic Stroke: Evidence from a Meta-Analysis

“…Nevertheless, the mechanism of ischemic stroke has not been fully elucidated and may involve a complex interplay between environmental and genetic factors, such as polymorphic variants of the genes that regulate cholesterol and lipid biosynthesis or degradation 2 . Emerging lines of evidence revealed that lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) and proprotein convertase subtilisin/kexin 9 (PCSK9) play critical roles in hyperlipidemia and atherogenesis development, that ultimately leads to ischemic stroke 3 4 .…”

“…PCSK9 binds to low density lipoprotein receptor (LDLR) and disrupts its endocytic recycling or directs it for lysosomal degradation 16 17 . Therefore, PCSK9 activation can downregulate LDLR expression and inhibit the uptake of LDL-C, which in turns leading to hypercholesterolemia and ischemic stroke event 4 18 .…”

Genetic Markers for Coronary Artery Disease

“…The gene which encodes for the PCSK9 is located on chromosome 1 [52,53] and encodes for the member of the subtilisin-like proprotein convertase family that activates other proteins, and its coding region is comprised of 13 exons [52]. In 2003, through the protein BLAST program [54], a putative convertase called neural apoptotic-regulated convertase 1 (NARC-1), which belongs to the proteinase L subfamily of subtilases, was identified [55].…”