Pravastatin attenuates interferon-gamma action via modulation of STAT1 to prevent aortic atherosclerosis in apolipoprotein E-knockout mice.

1. The beneficial effects of pravastatin, beyond that of lowering cholesterol in atherosclerosis, include reducing the action of interferon (IFN)-gamma. Interferon-gamma activates the signal transducer and activator of transcription 1 (STAT1), but it is unclear whether the inhibitory effect of pravastatin in atherosclerosis is via modulation of the IFN-gamma/STAT1 pathway. Thus, the aim of the present study was to determine whether the action of pravastatin in preventing aortic atherosclerosis by attenuation of IFN-gamma action is dependent on STAT1. 2. Male apolipoprotein E-knockout (apoE(-/-)) mice were fed a diet containing 1.25% cholesterol (w/w). Mice were divided into two groups, one of which was supplemented with pravastatin (80 mg/kg per day). Male C57BL/6J mice were fed a normal diet and served as the control group (n = 12 per group). 3. Atherosclerotic lesions in the aortic root were assessed by staining sections haematoxylin and eosin. Serum concentrations of IFN-gamma and IFN-gamma mRNA expression in the thoracoabdominal aorta were determined by ELISA and real-time quantitative polymerase chain reaction methods, respectively. Expression of phosphorylated STAT1 (pSTAT1), interferon regulating factor (IRF)-1 and suppressors of cytokine signalling 1 (SOCS1) was determined in the thoracoabdominal aorta using Western blot analysis. 4. After 8 weeks, pravastatin treatment significantly prevented the formation of atherosclerotic lesions (P < 0.05) and reduced serum IFN-gamma concentrations (P < 0.05) and levels of IFN-gamma mRNA within the aorta (P < 0.01). Pravastatin significantly decreased the expressions of pSTAT1 and IRF-1 within the aorta and significantly increased expression of SOCS1. 5. These results suggest that the actions of pravastatin in attenuating the action of IFN-gamma and subsequently preventing aortic atherosclerosis may depend, at least in part, on modulation of STAT1 activity. This providing us with a new therapeutic approach and a clearer insight into the clinical benefits of pravastatin.