Role of nitric oxide and CCAAT/enhancer-binding protein transcription factor in statin-dependent induction of heme oxygenase-1 in mouse macrophages

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 (EC 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,