Natalia Pauli, Monika Rać

PCSK9 - new perspectives for lipid-lowering pharmacotherapy in patients with coronary artery disease
2020-07-28

PCSK9 - new perspectives for lipid-lowering pharmacotherapy in patients with coronary artery disease

Optimal hypolipemic therapy reduces the risk of cardiovascular death. The drugs used in Poland are: statins, ion exchange resins, cholesterol absorption inhibitors, fibrates and proprotein subtylsin/cexin type 9 converting enzyme inhibitors (PCSK9). The function of PCSK9 is to bind receptors for LDL (LDLR) and reduce their amount in cell membrane, mainly hepatocytes and in circulation. The gene encoding PCSK9 is located on chromosome 1p32.3. The mature transcript consists of 12 exons, 692 amino acids. PCSK9 is synthesised as a zymogen and consists of several domains. The N-domain is a catalytic site inhibitor causing the mature PCSK9 protein to be catalytically neutral. PCSK9 acts through the transcription factor SREBP-2 - a protein that binds steroid response sequences. It is a mechanism of regulation through feedback. The LDLR receptor contains a domain structurally similar to the epithelial growth factor EGF-A, which is essential for recirculating the receptor from the endosome to the cell membrane. PCSK9 binds to this fragment of LDLR. Binding of EGF-A fragment by PCSK9 leads to internalisation of LDLR and its retention in the cell followed by degradation in lysosomes. A slightly different mechanism of action of PCSK9 is also possible. It binds inside the LDLR cell which has been internalized after the LDL particle has been attached. Then such a complex is degraded in the lysosome. The expression of PCSK9 promotes apoB100 secretion in liver cells. Thus, PCSK9 provides homeostasis in intracellular cholesterol transport. The polymorphism of a single nucleotide of PCSK9 gene associated with overexpression of PCSK9 protein leads to increased LDLR degradation in lysosomes. Decreasing the amount of LDLR results in a decrease in the receptor capture of LDL particles and prolongation of their retention in plasma. In this situation, LDL particles may undergo chemical modification (oxidation, glycosylation) and damage endothelial cells. Inhibition of PCSK9 gene expression or inhibition of PCSK9 activity is the aim of therapy in the treatment of hypercholesterolemia and its complications. The drugs injected are interfering RNA and monoclonal antibodies. Studies confirm that by reducing the activity of SREBP-2, PCSK9 inhibitors are effective in reducing plasma LDL concentration, not only preventing LDLR degradation, but also reducing PCSK9 itself from liver. Thus, they reduce the risk of cardiovascular death or the need for hospitalization due to unstable coronary disease and coronary revascularization. The knowledge of molecular basis of PCSK9 and its inhibitors seems important in clinical practice due to the need of using these drugs in the treatment of lipid disorders, in accordance with the current cardiologic standards.

Keywords: hypercholesterolemia, proprotein subtylsine-type 9 subtylsine-cexin converter, PCSK9 inhibitors.

© Farm Pol, 2020, 76 (6): 312–317