Abstract 331: Angiotensinogen Inhibition by Antisense Oligonucleotides Decreases Atherosclerosis and Obesity in a Dose-Dependent Manner

Abstract

Background and Objective: The renin-angiotensin system (RAS) exerts profound effects on experimental atherosclerosis. While there is evolving evidence of the complexity of the RAS, angiotensinogen (Agt) remains the single precursor for all known angiotensin peptides. The aim of this study was to determine the dose-dependent effects of inhibiting Agt synthesis on atherosclerosis. Methods and results: Male LDL receptor -/- mice were fed a saturated fat-enriched diet (21% wt/wt milk fat; 0.2% wt/wt cholesterol) for 3 months. Mice were injected weekly i.p. with either an antisense oligonucleotide (ASO) to Agt (ISIS #261333 at 50 mg/kg/week or #487022 at 12.5, 25 and 50 mg/kg/week) or a control ASO (ISIS #141923 at 50 mg/kg/week; n=10 mice per group). Administration of Agt ASO led to ∼90% reduction in plasma Agt concentrations (P<0.001) and a marked reduction in hepatic Agt mRNA abundance (P<0.05). There was also an expected dose-dependent increase in plasma renin concentrations (P<0.001). Agt ASO administration also decreased systolic blood pressure (SBP) in a dose-dependent manner (P<0.05). Inhibition of Agt significantly decreased total plasma cholesterol concentrations in the two highest dose Agt ASO groups. Atherosclerotic lesion areas were markedly decreased by Agt ASO administration in highest dose groups when compared to the PBS group (16.9 ± 1.0 versus 6.0 ± 1.3 and 6.2 ± 1.1 % of intimal area; P<0.001). Unexpectedly, Agt ASO administration also markedly attenuated body weight gain. MRI analyses demonstrated a dose-dependent reduction in fat mass (P<0.001) with no effect on lean mass. Adipose (retroperitoneal, inguinal and subcutaneous) tissue weights were decreased in a dose-dependent manner. Conclusions: Inhibition of Agt synthesis markedly decreases SBP, development of atherosclerosis and body weight gain in a dose-dependent manner.