Anti-Inflammatory Activity of Ezetimibe by Regulating NF-κB/MAPK Pathway in THP-1 Macrophages

Abstract

Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are involved in the inflammatory process during atherogenesis. Here, we performed daily gavage of ezetimibe in apolipoprotein E-deficient mice fed with a high-fat diet and found that ezetimibe administration decreased the level of C-reactive protein significantly. To investigate the potential molecular mechanism, we employed microarray analysis on the cultured macrophages treated with Chol:MßCD in the presence or absence of ezetimibe. We found that ezetimibe dramatically down-regulated the expression of the tumor necrosis factor-a (TNF-a) gene. Consistent with the microarray results, TNF-a protein levels were inhibited by ezetimibe. Moreover, ezetimibe suppressed the promoter activity of TNF-a but not TNF-a lacking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) binding domain in THP-1 cells treated with phorbol myristate acetate and Chol:MßCD. Furthermore, treatment of THP-1 macrophages with ezetimibe resulted in the degradation of IκB and subsequently inhibited nuclear translocation of NF-κB and its transcriptional activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway using PD98059 attenuated the reduction effect of ezetimibe on the expression of NF-κB. Collectively, our results demonstrated that the anti-inflammatory properties of ezetimibe in THP-1 macrophages are, at least in part, through suppression of NF-κB activation via the MAPK pathway. These data provide direct evidence for the potential application of ezetimibe in the prevention and treatment of inflammatory diseases.

Comparison of Renal Effects of Ezetimibe–Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis

“…It has been reported that ezetimibe confers additional beneficial effects other than lowering blood lipid levels. In animal models, ezetimibe reduced inflammatory response [50][51][52] and promoted autophagy, which resulted in neuroprotection or improvement of nonalcoholic fatty liver disease (NAFLD) [24,53] via AMP protein kinase (AMPK) activation and inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome [23]. In addition, ezetimibe is known to activate nuclear factor erythroid 2-related factor 2 (Nrf2) and to reduce oxidative stress in animal models [54].…”

Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition

“…This anti-inflammatory action of ezetimibe is partially consistent with a previous report showing that ezetimibe inhibited expression of CRP (C-reactive protein), TNF, and NFKB in THP-1 macrophages. 32 Recently, cell-cell interaction through exosomes was elucidated as a crucial factor in the development of NAFLD and NASH. 33 Exosomes, which contain proteins, mRNAs, and miR-NAs, are released by several cell types into biological fluids and taken up by endocytosis into different cell types.…”

Residual inflammatory risk in coronary heart disease: incidence of elevated high-sensitive CRP in a real-world cohort

“…This effect is likely based on both a distinct LDL-cholesterol reduction by combining statins with ezetimibe and an additional independent anti-inflammatory component as well [13,31]. Experimental data advise an ezetimibe-mediated inhibition of transendothelial monocyte migration threw regulation of the NF-κB/MAPK pathway in rabbits and mice as one potential mechanism [32,33]. Yet, additional pleiotropic, anti-inflammatory effects through statin therapy besides cholesterol reduction have already been demonstrated in a large clinical collective [6].…”