aliskiren and Aortic-Aneurysm--Abdominal

Angiotensin II is thought to participate in aneurysm formation, because of its ability to induce and perpetuate inflammation in the aortic wall. Because activation of renin is the first step of the renin-angiotensin system, renin inhibition could inhibit all components of this system effectively. Therefore, we examined the hypothesis that direct inhibition of renin activity could decrease the expansion of aortic aneurysm using a rabbit model. Aortic dilatation was induced by incubation with elastase around the rabbit abdominal aorta. Continuous administration of a direct renin inhibitor, aliskiren, was started at 1 week before incubation with elastase and continued for 5 weeks. Treatment with aliskiren markedly inhibited tissue renin activation and resulted in a significant reduction in angiotensin I and II production in the aneurysm wall. Consequently, the inhibition of renin activity prevented the expansion of experimental aortic aneurysm associated with preservation of the medial layer, independent of its blood pressure-lowering effect. Administration of aliskiren led to the inhibition of activation of NF-κB (nuclear factor-κB), AP-1 (activator protein-1), and CREB (cAMP response element-binding protein), which are thought to cooperatively regulate the inflammatory gene expression profile associated with aneurysm formation. As a result, treatment with aliskiren inhibited macrophage accumulation through suppression of MCP-1 (monocyte chemoattractant protein-1) and CCL4 (C-C motif chemokine ligand 4) expression, and TNF-α (tumor necrosis factor-α) production and activation of MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) were also suppressed in the aneurysm wall. In addition, inhibition of (pro)renin receptor elevation was also observed after treatment with aliskiren. Direct inhibition of renin activity using aliskiren prevented the progression of aortic aneurysm, suggesting it as a therapeutic option to treat abdominal aortic aneurysm.

Topics: Amides; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Blotting, Western; Disease Models, Animal; Disease Progression; Fumarates; Gene Expression Regulation; Immunoenzyme Techniques; Immunohistochemistry; Rabbits; Real-Time Polymerase Chain Reaction; Renin; Renin-Angiotensin System; RNA; Ultrasonography

Aliskiren is a direct renin inhibitor developed to treat hypertension. Several clinical studies have suggested that aliskiren has beneficial effects on cardiovascular diseases beyond its antihypertensive effect. In the present study, we examined whether aliskiren limits the progression of AAA (abdominal aortic aneurysm), VH (ventricular hypertrophy) and atherosclerosis in an AngII (angiotensin II)-infused mouse model. ApoE-/- (apolipoprotein-E-deficient) mice were infused subcutaneously with AngII (1000 ng/kg of body weight per day; 4 weeks) to induce AAA and VH. At the completion of the AngII infusion, mice were randomly allocated to three groups to receive vehicle control, low-dose aliskiren (10 mg/kg of body weight per day) or high-dose aliskiren (50 mg/kg of body weight per day) for 4 weeks. Suprarenal aortic diameter assessed by ultrasound was significantly smaller in mice administered aliskiren at days 42 and 56. Aliskiren also significantly reduced the normalized heart weight, ventricular myocyte cell width and aortic arch atherosclerosis. Aliskiren lowered PRR (pro-renin receptor) expression and MAPK (mitogen-activated protein kinase) activity in the suprarenal aorta and heart. Aortic infiltration of T-lymphocytes and macrophages was reduced by aliskiren. In conclusion, aliskiren limits the progression of AAA, VH and atherosclerosis in an AngII-infused mouse model.

Topics: Amides; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Fumarates; Hypertension; Hypertrophy; Mice; Mice, Inbred C57BL; Mice, Knockout