Abstract 444: Angiotensinogen Inhibition Reduces Atherosclerosis and Body Weight Gain Induced by High-Carbohydrate Diet

Abstract

Background and Objective: Angiotensinogen (AGT) is the unique precursor of the renin angiotensin system. Our previous studies demonstrated that inhibition of AGT markedly reduced development of atherosclerosis and ablated body weight gain induced by a saturated fat-enriched diet. In addition to high fat intake, high carbohydrate consumption is an important component of contemporary diets. The purpose of this study was to determine whether AGT inhibition prevented atherosclerosis and obesity in LDL receptor -/- mice fed a high carbohydrate diet. Methods and Results: Eight week old male LDL receptor -/- mice were randomized to receive either control or AGT antisense oligonucleotides (ASO; 50 mg/kg/week intraperitoneal injection; N = 10 mice/group). Feeding a high carbohydrate diet was initiated after 6 weeks of ASO injection, and maintained for 12 weeks with continuous ASO injection. AGT-ASO administration profoundly reduced plasma AGT concentrations (Control vs AGT ASO: 3582 ± 117 vs 227 ± 15 ng/ml; P<0.001). High carbohydrate diet feeding resulted in profound increases of plasma cholesterol concentrations in both groups. Atherosclerotic lesions in aortic arches were measured using an en face method after termination. AGT inhibition led to significant decreases (P<0.001) in percentage lesion areas of aortic arches. Prior to high carbohydrate diet feeding, there was no difference of body weight between the two groups (Control vs AGT ASO: 26.6 ± 0.6 vs 25.9 ± 0.7 g; P=0.4). Although high carbohydrate diet only increased body weight modestly, mice injected with AGT ASO had less increases of body weight compared to mice injected with control ASO (Control vs AGT ASO: 28.5 ± 0.6 vs 26.8 ± 0.6 g; P<0.05). Echo MRI analyses demonstrated that the lower body weight in mice administered AGT ASO was attributed to less fat mass gain, whereas lean mass was comparable between the two groups. Additionally, AGT inhibition resulted in lower blood hemoglobin A1c (5.5 ± 0.1 vs 5.1 ± 0.1%; P=0.005). Conclusions: AGT inhibition reduces high carbohydrate diet-induced atherosclerosis and body weight gain.