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

Abstract

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.

Ezetimibe treatment reduces oxidized low-density lipoprotein in biliary cirrhotic rats

“…Previous studies have reported that ezetimibe lacked obvious pleotropic effects compared to statins. 27 In contrast to many experiments confirming the pleiotropic effect of statins, there is still insufficient evidence of the pleiotropic effect of ezetimibe. 28 Similarly, our data showed that portal hypertension and hyperdynamic circulation could not be reversed by 4 weeks of ezetimibe treatment.…”

25-Hydroxycholesterol in health and diseases

“…Studies aiming to better deciphering these 25-HC/EC interactions used human umbilical vein ECs or pulmonary ECs and confirmed that high concentrations of 25-HC have deleterious effect on these cells and affects endothelial barrier permeability. Thus, treatment of human umbilical vein ECs with 25 μM of 25-HC decreases the cell index ( 108 , 109 ) and promotes production of a long list of inflammatory molecules (IL1β, IL-18, IL-23, EBI-3, IL-12, IL-35, TNF-α, and IL-6) or molecules involved in cell growth or immune responses (ICAM-1, MCP-1, VEGF) by ECs ( 80 , 109 , 110 ). On the contrary, production of anti-inflammatory molecules TGF-β, IL-10, and IL-37 is decreased ( 109 ).…”

“…On the contrary, production of anti-inflammatory molecules TGF-β, IL-10, and IL-37 is decreased ( 109 ). These downregulation or upregulations are reverted by several drugs including rosuvastatin, ezetimibe, rivaroxaban, and atorvastatin, all known to also targeting the cholesterol metabolism ( 109 , 110 , 111 ). As mentioned previously, 25-HC increase provokes a loss of the lung EC barrier integrity by disorganizing VE-cadherin assembly ( 54 ).…”

Lipid-Lowering Therapy after Acute Coronary Syndrome

“…They also encompass anti-inflammatory effects that inhibit cell proliferation, reduce the aggregation of inflammatory cells, and limit the secretion of pro-inflammatory cellular factors. Furthermore, statins have shown a pronounced impact on plaque stabilization and reduction, an effect considered to be linked to their anti-inflammatory capabilities [62][63][64].…”

“…In summary, the pleiotropic effects of statins contribute significantly to their cardioprotective role following ACS, offering benefits beyond lipid lowering. These effects include improving endothelial function, reducing vascular inflammation, and mitigating platelet activity, all of which are vital in reducing the incidence of periprocedural cardiac myonecrosis and the overall burden of cardiovascular disease post-PCI [61][62][63][64][65].…”