Effect of agonist of angiotensin-(1-7) on atherogenesis in apolipoprotein E-knockout mice

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Objective To investigate the effects of agonist of angiotensin-(1-7)(AVE0991) on endothelial function and atherogenesis in apolipoprotein E-knockout(ApoE-/-)mice. Methods Eight-week-old ApoE-/- male mice and C57BL/6J male mice were randomly divided into 3 groups: a normal diet control group(ND, n=10), a high-fat diet group(HFD, n=10), and a high-fat diet with AVE0991 0.58 μmol·kg-1·d-1group(HFD+ AVE0991, n=10). After 12 weeks of treatment, serum levels of lipids and parameters of endothelial function were measured.Atherosclerotic lesions in aorta roots were detected by Oil Red O staining.CD31 levels in the arterial intima were analyzed by immunohistochemistry. Results AVE0991 had no effects on blood lipids(P>0.05)but lowered serum levels of nitric oxide in high-fat diet mice(76.8±34.4 μmol/L vs.116.8±33.9 μmol/L, P 0.05)but decreased the activity of serum induced nitric oxide synthase(9.0±2.3 U/ml vs.12.7±3.2 U/ml, P<0.05)and increased the ratio of phosphorylated endothelial nitric oxide synthase to induced nitric oxide synthase in the vessel wall in high-fat diet mice(0.8±0.2% vs.0.6±0.2%, P<0.05). AVE0991 decreased serum levels of C-reactive protein, tumor necrosis factor-α and interleukin-6(P<0.05), and decreased the area percentage of atherosclerotic lesions in aorta roots(15.6±3.3% vs.45.4±9.8%, P<0.05)and increased the integrated optical density of CD31 in the arterial intima in high-fat diet mice(54.1±11.0% vs.28.7±10.6%, P<0.05). Conclusions AVE0991 can attenuate atherogenesis in ApoE-/- mice fed a high-fat diet, possibly via reducing inflammatory response, regulating the activity of nitric oxide synthases and improving endothelial functions. Key words: AVE0991; Angiotensins; Apolipoproteins; Atherogenesis; Nitric oxide synthase