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PRAVASTATIN ATTENUATES INTERFERON‐γ ACTION VIA MODULATION OF STAT1 TO PREVENT AORTIC ATHEROSCLEROSIS IN APOLIPOPROTEIN E‐KNOCKOUT MICE
Author(s) -
Zhou XiaoXu,
Gao PingJin,
Sun BaoGui
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.05067.x
Subject(s) - pravastatin , endocrinology , medicine , aorta , apolipoprotein b , stat1 , apolipoprotein e , cholesterol , receptor , disease
SUMMARY1 The beneficial effects of pravastatin, beyond that of lowering cholesterol in atherosclerosis, include reducing the action of interferon (IFN)‐γ. Interferon‐γ 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‐γ/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‐γ 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‐γ and IFN‐γ 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‐γ concentrations ( P < 0.05) and levels of IFN‐γ 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‐γ 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.