Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

Abstract

Background: Atherosclerosis is a disorder in which, in addition to high cholesterol levels, several plasma factors play a significant role in its development. Among these cytokines and molecules are interleukin 6 (IL-6), interleukin 18 (IL-18), tumor necrosis factor α (TNF-α), metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9), all of which may contribute to the stabilization of atherosclerotic plaque. The purpose of this study was to determine the effect of advanced lipid-lowering therapy on the levels of these determinants by utilizing proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in patients with verified high-risk atherosclerotic plaque. Methods: The study involved patients with dyslipidemia who had the presence of unstable atherosclerotic plaque verified by ultrasonography and who were eligible to begin alirocumab treatment. The levels of IL-6, IL, 18, TNF-α, and MMPs were determined in this group before and after three months of therapy. Results: After treatment, a statistically significant decrease in concentrations of Il-18, Il-6, TNF-α (p < 0.001) and MMP-2 (p < 0.05) was observed. Additionally, we observed that the concentrations of these markers were significantly higher in the group of patients prior to initiating therapy than in the control group. Conclusions: Our study’s results suggest that PCSK-9 inhibitor therapy significantly reduces the concentration of factors influencing the stability of atherosclerotic plaque, which may explain their essential importance in reducing cardiovascular risk in patients receiving this treatment.

The Anti-atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin – an Experimental Study

“…We also noticed a complementary pattern after bosentan and atorvastatin in the modulation of inflammatory mediators, focusing on TNF-a and MCP-1. Experimental and clinical data have supported the relationship of inflammation with atherosclerosis development and progression [41]. Previous studies have reported reduction of two multifunctional inflammatory agents, TNF-a and MCP-1 after statin administration [42,43].…”

SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells

“…Indeed, hs-CRP, a known marker of low-grade inflammation, is not affected by treatment with PCSK9i 33 . On the other hand, selected reports showed that treatment with PCSK9i might decrease circulating levels of IL-6 and of other cytokines 34 , 35 . Interestingly, also IL-6 inhibition has been reported to decrease circulating levels of PCSK9 protein 15 , possibly suggesting a bidirectional relationship.…”

Metformin Directly Binds to MMP-9 to Improve Plaque Stability

“…Both canakinumab and PCSK-9 inhibitors have anti-inflammatory effects. Moreover, PCSK-9 inhibitors also have an inhibitory effect on MMP-2, but cannot inhibit MMP-9 [ 30 ]. So, the mechanism by which canakinumab and PCSK-9 inhibitors stabilize plaques may be different from metformin.…”