title: Pravastatin attenuates interferon-gamma action via modulation of STAT1 to prevent aortic atherosclerosis in apolipoprotein E-knockout mice.
abstract: 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.
authors.affiliation: Department of Cardiology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, China.
authors.forename: Xiao-Xu
authors.initials: XX
authors.lastname: Zhou
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
authors.forename: Bao-Gui
authors.initials: BG
authors.lastname: Sun
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D000960:Hypolipidemic Agents; D050856:Interferon Regulatory Factor-1; D008055:Lipids; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D017035:Pravastatin