Abstract 1154: Renin Inhibition Markedly Reduces Hypercholesterolemia-Induced Atherosclerosis
Objective: Inhibition of the renin-angiotensin system reduces atherosclerotic lesion size in several hypercholesterolemic models of the disease. However, the interpretation of studies using ACE inhibitors may be confounded by possible effects on bradykinin metabolism. Also, the benefits of AT1 receptor antagonists may arise from the continued presence of angiotensin peptides interacting with alternative receptors (AT2, AT4, Mas). Renin acts specifically on angiotensinogen and is the rate-limiting enzyme in the synthesis of angiotensin peptides. Thus, inhibition of renin would decrease the effects of angiotensin peptides without confounding effects on other pathways. The purpose of this study was to determine the effects of the renin inhibitor, aliskiren, on the development of atherosclerosis in LDL receptor −/− mice.
Methods and Results: Male LDL receptor −/− mice (2 months of age) were administered either vehicle (n= 13) or aliskiren (25 or 50 mg/kg/day by osmotic minipump; n = 12/dose) for 3 months. All groups were fed a modified diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) for the duration of drug administration. Systolic blood pressure was reduced by both doses of aliskiren in LDL receptor −/− mice fed the modified diet (131 ± 2 mmHg in vehicle versus 113 ± 1 and 107 ± 3 mmHg for low and high doses; P<0.001). Renin inhibition was not associated with changes in serum total cholesterol concentrations or lipoprotein-cholesterol distribution. Also, no changes were noted in oxidant stress, as assessed by MDL-LDL autoantibody titers in serum and abundance of 12/15 lipoxygenase protein in macrophages. However, both doses of aliskiren led to a virtual ablation of the development of atherosclerotic lesions in both the aortic arch and root (for arch: 11.3 ± 1.1% of intimal area covered by lesions in vehicle infused versus 1.9 ± 0.4% and 1.9 ± 0.3% low and high doses, respectively; P<0.001).
Conclusion: Renin inhibition markedly decreased the development of hypercholesterolemia-induced atherosclerosis in LDL receptor −/− mice.