| ObjectTo study the effects of pravastatin on p38 MAPK, IFN-γ/STAT1 and IL-6/STAT3 signal pathway during preventing for atheroscleorisis and probe into anti-oxidative and anti-inflammatory mechanisms of pravastatin preventing for atherosclerosis, which may provide new therapeutic approaches for pravastatin preventing for atherosclerosis and clinical evidences for controlling atherosclerosis.Methods1) Male apoE-/- mice fed a chow diet containing 1.25% cholesterol (wt/wt) were divided into pravastatin group provided with pravastatin (80mg/kg per day) and atherosclerosis group provided without pravastatin. Eight weeks later, mice were anesthetized. Serum was saved. The excised aortic roots were examined for detailed histological analysis. The excised thoracoabdominal aortas were used for mRNA and protein analysis.2) Concentrations of total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) in serum were measured by Biochemistry Analyzer.3) Paraffin sections from the aortic root were stained with Hematoxylin and Eosin. The size of atherosclerotic lesion in each section was evaluated.4) Levels of IFN-γand TNF-αmRNA in thoracoabdominal aortas were examined by real-time PCR.5) Concentrations of IL-6, IFN-γand TNF-αin serum and the thoracoabdominal aorta and concentration of ox-LDL in serum were measured by ELISA.6) Activities of SOD, GSH-Px, CAT and GST and Concentrations of MDA and GSH in thoracoabdominal aorta were measured.7) Expressions of 3-nitrotyrosine, iNOS, p38 MAPK, p-p38 MAPK, p53, STAT1, pSTAT1, STAT3, pSTAT3, IRF-1 and SOCS1 in thoracoabdominal aorta were examined by Western Blot.Results1) Pravastatin may prevent for atherosclerosis induced by high-cholesterol diet in apoE-/- mice (P <0.05).2) Concetrations of LDL-c and TC in pravastatin group were not statistic differences compared with atherosclerosis group.3) Concentrations of IL-6 (P <0.01), IFN-γ(P <0.01) and TNF-α(P <0.01) and ox-LDL (P <0.05) in serum of apoE-/- mice were significantly decreased in pravastatin group.4) Levels of IFN-γand TNF-αmRNA in the thoracoabdominal aortas of apoE-/- mice were significantly reduced by pravastatin (P <0.05).5) Concentrations of IL-6 (P <0.01), IFN-γ(P <0.01) and TNF-α(P <0.05) in the thoracoabdominal aorta of apoE-/- mice were significantly decreased by pravastatin.6)The concentration of MDA was decreased (P <0.01) and the concentration of GSH was increased (P <0.01) in the thoracoabdominal aortas of apoE-/- mice by pravastatin respectively.7) Activities of SOD (P <0.01), GSH-Px (P <0.05), CAT (P <0.01) and GST (P <0.01) in the thoracoabdominal aortas of apoE-/- mice were enhanced by pravastatin.8) Expressions of 3-nitrotyrosine and iNOS in the thoracoabdominal aortas of apoE-/- mice were down-regulated by pravastatin.9) Expressions of p-p38 MAPK and p53, as the active form and downstream factor of p38 MAPK signal pathway respectively, in the thoracoabdominal aortas of apoE-/- mice were down-regulated by pravastatin.10) Expressions of pSTAT1 and pSTAT3, as active forms of IFN-γ/STAT1 and IL-6/STAT3 signal pathway respectively, and expression of IRF-1 as a downstream factor of IFN-γ/STAT1 pathway in the thoracoabdominal aortas of apoE-/- mice were down-regulated by pravastatin.11) The expression of SOCS1 as inhibitory factors of IFN-γ/STAT1 and IL-6/STAT3 signal pathway in the thoracoabdominal aortas of apoE-/- mice were down-regulated by pravastatin.Conclusions1,Pravastatin may prevent for atherosclerosis induced by high-cholesterol diet in apoE-/- mice.2,Concentrations of TC and LDL-c were increased in atherosclerosis, and pravavstatin could not decrease that concentrations. The effect of pravastatin preventing for atherosclerosis in apoE-/- mice may not depend on properties of lowering cholesterol.3,The balance between oxidant and antioxidant system was disturbed and inflammation was enhanced in atherosclerosis. Pravastatin may prevent for atherosclerosis by attenuating oxidative stress, nitrosative stress and inflammation.4,P38 MAPK signal pathway was activated in atherosclerosis. Pravastatin maybe modulate p38 MAPK signal pathway to prevent afor therosclerosis.5,IFN-γ/STAT1 signal pathway was activated in atherosclerosis. Pravastatin maybe modulate IFN-γ/STAT1 signal pathway to prevent for atherosclerosis.6,IL-6/STAT3 signal pathway was activated in atherosclerosis. Pravastatin maybe modulate IL-6/STAT3 signal pathway to prevent for atherosclerosis.
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