What is the clinical evidence from this study?

Study design: Other. Population: Hypercholesterolemia-induced atherosclerosis (n=51). Intervention: Aliskiren vs. Vehicle (PBS). Primary outcome: Atherosclerotic lesion size in the aortic root (p=<0.0001).

February 1, 2008Open Access

Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice

Q: What are the key findings of this study?

Renin inhibition with aliskiren profoundly reduced atherosclerotic lesion size in the aortic root of fat-fed Ldlr-/- mice in a dose-dependent manner compared to vehicle (p<0.0001).

Key Result

Renin inhibition with aliskiren profoundly reduced atherosclerotic lesion size in the aortic root of fat-fed Ldlr-/- mice in a dose-dependent manner compared to vehicle (p<0.0001).

Structured PICO

Does renin inhibition with aliskiren reduce atherosclerotic lesion size in fat-fed Ldlr(-/-) mice?

Population

51 male Ldlr-/- mice fed a fat-supplemented diet for 12 weeks to induce hypercholesterolemia and atherosclerosis.

Intervention

Aliskiren (renin inhibitor) via continuous subcutaneous infusion at 2.5, 25, or 50 mg/kg/d for 12 weeks; or bone marrow transplantation from renin-/- mice

Comparator

Vehicle (PBS) infusion; or bone marrow transplantation from renin+/+ mice

Outcome

Atherosclerotic lesion size in the aortic arch and aortic rootsurrogate

Systemic renin inhibition with aliskiren profoundly reduces hypercholesterolemia-induced atherosclerosis in mice, independent of blood pressure reduction.

Main Result

Absolute Event Rate: 0.05% vs 0.16%

p-value: p=<0.0001

Limitations

Animal model findings may not directly translate to human clinical outcomes.
Direct comparisons of the efficacy of renin inhibition, AT1 receptor blockade, and ACE inhibition on reduction in atherosclerotic lesion size were not performed within a single study.

Abstract

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr(-/-)) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr(-/-) mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.

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