Abstract 5457: Angiotensinogen Hypomorphic Mice Have Markedly Reduced Hypercholesterolemia-induced Atherosclerosis
Background and Objective: The renin angiotensin system exerts profound effects on experimental atherosclerosis. Although multiple enzymes are proposed to generate the increasingly complex array of angiotensin peptides, angiotensinogen is the unique precursor of all angiotensin peptides. Angiotensinogen deficiency in mice leads to poor neonatal survival rate and multiple organ dysfunctions that present barriers to atherosclerosis studies. Therefore, we generated a hypomorphic angiotensinogen (hypoAGT) mouse model to determine the effects of reduced angiotensinogen on atherosclerosis in LDL receptor −/− mice.
Methods and Results: hypoAGT mice were developed by insertion of a neomycin resistance cassette in the second intron of the angiotensinogen gene. Although hypoAGT mice have almost undetectable plasma angiotensinogen concentrations and markedly higher renin concentrations compared to the wild type control, these mice have normal neonatal survival rate and grossly normal growth development. To determine the contribution of angiotensinogen to atherosclerosis, male wild type and hypoAGT mice in an LDL receptor −/− background were fed a saturated fat-enriched diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) for 12 weeks. Body weight was monitored weekly. hypoAGT mice had modestly lower body weight at the initiation of the study. When fed the saturated fat-enriched diet for 12 weeks, wild type mice increased body weight by 49% compared to a 6% increase in hypoAGT mice. Systolic blood pressure (SBP) was measured using a non-invasive tail-cuff system on conscious mice. hypoAGT mice had lower SBP at baseline and when fed the saturated fat-enriched diet. Both wild type and hypoAGT mice were hypercholesterolemic, although hypoAGT mice had lower plasma cholesterol concentrations (wild type versus hypoAGT: 2789±115 versus 1647±106 mg/dl). Atherosclerotic lesion areas were measured on the intima of the aortic arch by the en face technique. hypoAGT mice had a virtual ablation of the development of atherosclerotic lesions (wild type versus hypoAGT: 20.5±2.4 versus 1.1±0.8%).
Conclusion: Profound reduction of angiotensinogen strikingly attenuates development of hypercholesterolemia-induced atherosclerosis in LDL receptor −/−mice.