Regulation of PCSK9 During Oxidized LDL-Induced Foam Cell Formation in RAW264.7 Cells

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is traditionally known for regulating plasma LDL cholesterol levels via LDL receptor degradation. This exploratory study examined the association between chemically induced changes in Krüppel-like factor 2 (KLF2), a vasoprotective transcription factor, and PCSK9 expression under ox-LDL-induced conditions in RAW264.7 cells. In silico molecular docking was also performed to determine whether GGTI298 could adopt a predicted binding pose within PCSK9. KLF2 was modulated by adding GGPP (a chemical inhibitor) and GGTI298 (a chemical activator) to the monocytes. Quantitative real-time PCR and immunocytochemistry were used to assess KLF2 and PCSK9 expression. Molecular docking was performed to examine the interaction between GGTI298 and PCSK9 using computational tools. Results show that ox-LDL significantly increased PCSK9 expression in monocytes during foam cell formation. However, GGPP significantly increased PCSK9 expression. In contrast, GGTI298 markedly reduced PCSK9 expression, suggesting a negative regulatory role of KLF2. Docking studies revealed that GGTI298 binds to the PCSK9 catalytic domain with favorable binding energy, forming stable hydrogen bonds and hydrophobic interactions with key amino acid residues, indicating potential interference with PCSK9 function. GGTI298 suppresses PCSK9 expression during foam cell formation, highlighting its protective role. The dual ability of GGTI298 to enhance KLF2 expression and directly bind to PCSK9 underscores its potential as a therapeutic agent for managing foam cell formation that leads to atherosclerosis. The findings demonstrate an inverse association between KLF2 and PCSK9 expression following chemical treatment under ox-LDL-induced conditions. However, direct KLF2-dependent regulation of PCSK9, direct GGTI298-PCSK9 binding, and functional inhibition of PCSK9 were not established and require further genetic, biochemical, and functional validation.