PCSK9 signaling pathways and their potential importance in clinical practice
Proprotein convertase subtilisin/kexin 9 (PCSK9), a member of the protein-converting enzyme family, is highly expressed in adult hepatocytes and small intestinal enterocytes. To our knowledge, in this study, we demonstrate for the first time that PCSK9 is upregulated in a dose-dependent manner via oxidized low-density lipoprotein (oxLDL) stimulation in THP-1-derived macrophages. PCSK9 small interfering RNA (siRNA) suppresses the oxLDL-induced inflammatory cytokine expression in THP-1-derived macrophages. The exposure of macrophages to oxLDL markedly increased the expression of NF-κB protein in the nucleus. However, this effect was significantly attenuated by PCSK9 siRNA. These findings indicate that PCSK9 expression is induced by oxLDL, and that PCSK9 siRNA protects against inflammation via the inhibition of NF-κB activation in oxLDL-stimulated THP-1-derived macrophages. Our results suggest that PCSK9 may be used as a therapeutic target for the treatment of atherosclerosis since PCSK9 siRNA suppresses oxLDL-induced IκB-α degradation and NF-κB nuclear translocation into THP-1-derived macrophages.