Simvastatin Inhibits C-Reactive Protein-Induced Pro-Inflammatory Changes in Endothelial Cells by Decreasing Mevalonate Pathway Products

Abstract

Objectives: The effects of HMG-CoA reductase inhibitors on C-reactive protein (CRP)-induced pro-inflammatory changes in endothelial cells remain unclear. We tested the hypothesis that simvastatin inhibited CRP-induced pro-inflammatory changes in endothelial cells by decreasing mevalonate pathway products. Methods: Human umbilical vein endothelial cells were incubated with CRP and measurement of CD32, nuclear factor ĸB (NF-ĸB) activation, vascular cell adhesion molecule-1 expression and monocyte adhesion assay were performed. The effects of simvastatin, siRNA against CD32 (siCD32) and mevalonate pathway products were also examined. Results: Pre-treatment with simvastatin significantly attenuated the CRP-induced CD32 expression and NF-ĸB activation in human umbilical vein endothelial cells. Simvastatin also decreased CRP-induced vascular cell adhesion molecule-1 expression and reduced monocyte adhesion on endothelial cells. The inhibitory effects of simvastatin were significantly reversed by adding mevalonate and geranylgeranyl pyrophosphate (GGPP), but not by adding farnesyl pyrophosphate. Pre-treatment with siCD32 also decreased CRP-induced CD32 expression and inhibitor of ĸB degradation. However, neither mevalonate nor GGPP reversed the effects of siCD32. Conclusions: CRP-induced CD32 expression and NF-ĸB activation were attenuated by simvastatin. A decrease in mevalonate and subsequent GGPP contributes to the inhibitory effects of simvastatin. These findings may provide an explanation of using statins on patients with high serum CRP levels.

Lack of modulatory effect of simvastatin on indoxyl sulfate-induced activation of cultured endothelial cells

“…A lack of protection against IS-associated endothelial damage suggests that endothelial injury is induced by IS via a pathway that was not affected by simvastatin. Previous studies have demonstrated the beneficial effect of simvastatin on C-reactive protein, tumor necrosis factor α, and the oxidized lipoprotein-induced activation of endothelial cells (Schaefer et al, 2004;Zapolska-Downar et al, 2004;Liang et al, 2008). The concentration of simvastatin used in our study was comparable to that of other studies and the duration of simvastatin pre-treatment was also similar.…”

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

“…Moreover, statin treatment can result in both circulating CRP and mononuclear cell FOS mRNA downregulation (16). Simvastatin may also inhibit NF-B-mediated effects of CRP on monocyte adhesion to EC and adhesion molecule expression by EC (24,26). Although statin treatment did not show any significant effects on primary outcome in CTEPH patients (55), it significantly decreases the risk of recurrent pulmonary embolism (3), a risk factor for CTEPH.…”

Medium-Term Exposure to Traffic-Related Air Pollution and Markers of Inflammation and Endothelial Function

“…Prospective and randomized clinical trials, as well as laboratory studies, have demonstrated that statins, a widely prescribed class of drugs with anti-inflammatory and antioxidant activity (Haendeler et al 2004), can decrease C-reactive protein (CRP), ICAM-1, and VCAM-1 levels (Albert et al 2001; Blanco-Colio et al 2007; Liang et al 2008; Montecucco et al 2009). Thus, it is plausible that statin use could attenuate proinflammatory effects of air pollution, and reduced effects of air pollution on inflammation and heart-rate variability among statin users compared with nonusers have been reported (Schwartz et al 2005; Zeka et al 2006).…”