Abstract 456: Comparative Effects of Angiotensinogen versus Renin Inhibition on Established Atherosclerosis and Obesity in Hypercholesterolemic Mice

Abstract

Background and Objective The renin angiotensin system plays a critical role in atherosclerosis. Inhibition of angiotensinogen (AGT) or renin prevents atherosclerosis. AGT inhibition also ablates diet induced obesity. The purpose of this study was to compare the effects of AGT and renin inhibition on established atherosclerosis and obesity. Methods and Results To determine the role of AGT, male LDL receptor -/- mice were fed a saturated fat-enriched diet for 12 weeks to establish atherosclerosis (N=80). Body weight increased about 1 g/week in the 12-week duration. Twenty mice were then terminated to assess baseline atherosclerosis, and the remaining mice were randomly grouped to administer either control- or AGT-antisense oligonucleotides (ASO) (50 mg/kg/week ip; N=20/group) for 12 weeks. To determine the role of renin inhibition, male LDL receptor -/- mice were fed the same fat-enriched diet for 16 weeks (N=55). Mean body weight gain was about 1 g/week. Twenty-one mice were terminated to assess baseline atherosclerosis, and the remaining mice were randomly grouped to infuse either PBS (N=24) or aliskiren (12.5 mg/kg/d; N=10) for 12 weeks. Inhibition of AGT or renin significantly decreased systolic blood pressure. Atherosclerotic lesions were quantified in the aortic arch. Inhibition of either AGT or renin attenuated the rogression of atherosclerosis as compared to their relative controls (P=0.047 and P≤0.001, respectively), whereas neither mode of inhibition regressed atherosclerosis compared to their respective baseline. Renin inhibition did not influence the fat diet-induced body weight gain. Surprisingly, inhibition of AGT not only abolished body weight gain, but also led to pronounced loss of body weight (baseline versus 12-week injection of AGT-ASO: 36.0±0.8 versus 32.2±0.9 g; P<0.001). Echo MRI analyses demonstrated that the lower body weight in mice administered AGT-ASO was attributed to less fat mass, while lean mass was comparable between control-ASO and AGT-ASO groups. Conclusions Inhibition of either AGT or renin attenuated the continued development of atherosclerosis. Inhibition of AGT also profoundly reduced body weight. This highlights a disparity between the two modes of RAS inhibition.