The effect of lipid-lowering therapies on the pro-inflammatory and anti-inflammatory properties of vascular endothelial cells

by Selleckchem | Mar 16 2023

Atherosclerosis and cardiovascular events can be prevented, or treated, using statin therapy, either alone or in combination with ezetimibe. Chronic inflammation, vascular proliferation, and the development of atherosclerosis are also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe, and their combinations, on the mRNA expression of pro-inflammatory IL1β, IL-18 and IL-23 and anti-inflammatory TGFβ, IL-35 (EBI3, IL-12 subunits), IL-10 and IL-37, in endothelial cells damaged by 25-OHC. It also analyzed IL-35 expression at the protein level. HUVECs were stimulated with atorvastatin (5 μM), rosuvastatin (10 μM), ezetimibe (1.22 μM), atorvastatin-ezetimibe (5 μM + 1.22 μM) or rosuvastatin-ezetimibe (10 μM + 1.22 μM), with or without pre-incubation with 10 μg/mL 25-OHC. mRNA expression was analyzed by real-time PCR. The protein level of IL-35 was analyzed by ELISA. In the pre-stimulated HUVECs, atorvastatin and rosuvastatin decreased mRNA expression of IL1β, IL-18, IL-23, TGFβ, IL35 and increased mRNA expression of IL-10 and IL-37 compared to 25-OHC. Furthermore, only incubation with rosuvastatin and rosuvastatin-ezetimibe decreased IL-35 mRNA and protein levels. Ezetimibe down-regulated only IL1β. Treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe reversed the effect of 25-OHC in IL1β, IL-18 and IL-35 mRNA expression. In conclusion, rosuvastatin has the strongest anti-inflammatory effects and is the best at reducing the effect of oxysterols. Both statins exert a greater anti-inflammatory effect than ezetimibe. The anti-inflammatory effect of the combination therapies appears to be based on the effects of the statins alone and not their combination with ezetimibe.

Comments：

The study aimed to compare the effects of atorvastatin, rosuvastatin, ezetimibe, and their combinations on the mRNA expression of pro-inflammatory and anti-inflammatory markers in endothelial cells damaged by 25-hydroxycholesterol. The study found that both statins, atorvastatin, and rosuvastatin, had a stronger anti-inflammatory effect than ezetimibe. Rosuvastatin had the strongest anti-inflammatory effect and was the best at reducing the effect of oxysterols. Both statins decreased the mRNA expression of pro-inflammatory markers (IL1β, IL-18, IL-23) and increased the mRNA expression of anti-inflammatory markers (TGFβ, IL-10, IL-37) compared to 25-OHC. Rosuvastatin and rosuvastatin-ezetimibe decreased both mRNA and protein levels of IL-35. Ezetimibe down-regulated only IL1β. Treatment with atorvastatin-ezetimibe and rosuvastatin-ezetimibe reversed the effect of 25-OHC on IL1β, IL-18, and IL-35 mRNA expression. The anti-inflammatory effect of the combination therapies appears to be based on the effects of the statins alone and not their combination with ezetimibe.

These findings suggest that statins, particularly rosuvastatin, may have pleiotropic effects beyond their lipid-lowering effects that could be beneficial in preventing or treating atherosclerosis and cardiovascular events. However, further studies are needed to confirm these findings and to investigate the clinical significance of these pleiotropic effects.