ABSTRACT
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-1 group(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).Also,AVE0991 had no effects on the activity of serum nitric oxide synthase(19.5±5.7 U/ml vs.17.9±3.3 U/ml,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.
ABSTRACT
Present study was designed to investigate the possible involvement of leptin in the pharmacological activation of Mas–receptor in STZ-diabetic rats, with cardiomyopathy. A single administration of STZ (50 mg/kg, i.p.) produced diabetes which leads to cardiomyopathy after 8 weeks. Estimation of serum glucose has been used as a marker of hyperglycemia. Cardiomyopathy was assessed by measuring LV collagen content, absolute LV weight, LVW/BW ratio, LVDP, dp/dtmax and dp/dtmin. Furthermore, serum triglyceride, serum cholesterol and serum HDL levels were estimated as an index of dyslipidemia. Rat serum leptin was quantitatively estimated by using enzyme-linked immunosorbent assay (ELISA) kit. STZ-diabetic rats were associated with significant hyperglycemia, hypertriglyceridemia, decreased cardiac functions and decreased serum leptin level. Both the low and high dose AVE-0991 treatment, significantly decreased hyperglycemia and increased serum leptin level in diabetic rats. Whereas, AVE-0991 only at high dose significantly improved lipid profile and cardiac function. on the basis of above, it may be concluded that downstream activation of leptin may be responsible for the beneficial effect of AVE-0991, a Mas-receptor agonist in STZ-induced diabetic cardiomyopathy in rats.