Abstract
The effect of statins on heme oxygenase-1 (HO-1) was compared in 2 murine cell lines, RAW 264.7 and J774A.1 cell lines, and in primary peritoneal macrophages of BALB/c or C57BL/6 mice. The role of endogenous nitric oxide and the type of transcription factors involved were explored. Simvastatin and fluvastatin induced HO-1. Pretreatment of cells with l-NMMA or 1400 W, two different nitric oxide synthase inhibitors, partially blocked statin-dependent induction of HO-1 in RAW 264.7 and J774A.1 but not in primary peritoneal macrophages. Induction of HO-1 by statins was dependent on p-38 MAP kinase activation in all types of macrophages. In RAW 264.7 cells, both statins increased the activity of reporter genes linked to the proximal 1.3 kbp promoter of HO-1 (EC50 of 1.4±0.3 µM for simvastatin and 0.6±0.03 µM for fluvastatin). This effect was significantly blocked by 1400 W (80±5.2% inhibition, p<0.02) and mevalonate, the direct metabolite of HMGCoA reductase. Gel retardation experiments implicated C/EBPβ, AP-1 but not USF, for both RAW 264.7 and primary peritoneal macrophages of C57BL/6 mice. Collectively we showed a differential role of endogenous nitric oxide between macrophage cell lines and primary macrophages and an effect of statins in the protection against inflammation by increasing HO-1 expression.
Highlights
Statins are lipid-lowering agents that act as competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase [1]
Since macrophages are important players in inflammation and since statins were shown to have anti-inflammatory effects, we aimed to study the regulation of heme oxygenase-1 (HO-1) and the mechanisms underlying this regulation in different types of macrophages, primary cells and murine cell lines, mainly by investigating the role of endogenous nitric oxide (NO) and the transcription factors involved
Induction of HO-1 was slightly detectable at 5 mM simvastatin and 2 mM fluvastatin; maximal statistically significant induction was observed with 25 mM simvastatin and 10 mM fluvastatin (2.960.5 and 2.360.3 fold of HO-1 expression of control, mean 6 S.E.M., n = 4, p,0.005 and p,0.01, t-test, for simvastatin and fluvastatin, respectively)
Summary
Statins are lipid-lowering agents that act as competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase [1]. It has been shown that statins decrease the production of proinflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)a [3,4] and monocyte chemoattractant protein MCP-1 [5], expression of adhesion molecule, tissue factor [6] as well as cyclooxygenase-2 and prostaglandin synthesis [7] Some of these beneficial effects, such as the improvement of endothelial function and anti-oxidant capacities were demonstrated in vivo [8]. Since macrophages are important players in inflammation and since statins were shown to have anti-inflammatory effects, we aimed to study the regulation of HO-1 and the mechanisms underlying this regulation in different types of macrophages, primary cells and murine cell lines, mainly by investigating the role of endogenous NO and the transcription factors involved
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