Renin Inhibition by Aliskiren Prevents Atherosclerosis Progression

Abstract

Abstract-Hypertension is associated with increased risk of cardiovascular diseases. Antihypertensive treatment, particularly blockade of the renin-angiotensin system, contributes to prevent atherosclerosis-mediated cardiovascular events. Direct comparison of different antihypertensive treatments on atherosclerosis and particularly plaque stabilization is sparse. ApoE Ϫ/Ϫ mice with vulnerable (2-kidney, 1-clip renovascular hypertension model) or stable (1-kidney, 1-clip renovascular hypertension model) atherosclerotic plaques were used. Mice were treated with aliskiren (renin inhibitor), irbesartan (angiotensin-receptor blocker), atenolol (␤-blocker), or amlodipine (calcium channel blocker). Atherosclerosis characteristics were assessed. Hemodynamic and hormonal parameters were measured. Aliskiren and irbesartan significantly prevented atherosclerosis progression in 2-kidney, 1-clip mice. Indeed, compared with untreated animals, plaques showed thinner fibrous cap (PϽ0.05); smaller lipid core (PϽ0.05); decreased media degeneration, layering, and macrophage content (PϽ0.05); and increased smooth muscle cell content (PϽ0.05). Interestingly, aliskiren significantly increased the smooth muscle cell compared with irbesartan. Despite similar blood pressure lowering, only partial plaque stabilization was attained by atenolol and amlodipine. Amlodipine increased plaque smooth muscle cell content (PϽ0.05), whereas atenolol decreased plaque inflammation (PϽ0.05). This divergent effect was also observed in 1-kidney, 1-clip mice. Normalizing blood pressure by irbesartan increased the plasma renin concentration (5932Ϯ1512 ng/mL per hour) more than normalizing it by aliskiren (16085Ϯ5628 ng/mL per hour). Specific renin-angiotensin system blockade prevents atherosclerosis progression. First, evidence is provided that direct renin inhibition mediates atherosclerotic plaque stabilization. In contrast, ␤-blocker and calcium channel blocker treatment only partially stabilize plaques differently influencing atherogenesis. Angiotensin II decisively mediates plaque vulnerability. The plasma renin concentration measurement by an indirect method did not confirm the excessive increase of plasma renin concentration reported in the literature during aliskiren compared with irbesartan or amlodipine treatment. (Hypertension. 2008;51:1306-1311.)

Effects of Restoration of Blood Flow on the Development of Aortic Atherosclerosis in ApoE −/− Mice With Unilateral Renal Artery Stenosis

“…There was significant macrophage expression within atheroma from mice with chronic RAS (Figure 5A), consistent with previous studies showing that chronic RAS is associated with a vascular inflammatory reaction 10, 11, 16. Macrophages were detectable within atheroma from mice in the D4LR and D8LR groups, but at levels significantly less than observed in atheroma from mice in the chronic RAS group (Figure 5B).…”

“…Abdominal aortic atheroma were present in mice in the D4LR, D8LR, and chronic RAS groups, whereas there were no atheroma in the 16 mice that underwent sham surgery. There was significant accumulation of macrophages within atheroma in the chronic RAS group, consistent with past studies that showed pronounced inflammatory response in the aorta 4 weeks10, 11 and 90 days16 after unilateral renal artery clipping in ApoE −/− mice. Restoration of renal blood flow either 4 or 8 days after unilateral partial RAS was associated with lower levels of macrophage infiltration than chronic RAS, strongly suggesting that restoration of renal blood flow has an anti‐inflammatory effect.…”

“…These lesions progress with age in chow‐fed mice, such as used in the present study. Interventions such as a high‐fat, high‐cholesterol diet,20 infusion of Ang II,6, 8 and unilateral RAS10, 11, 16, 21 have been shown to accelerate lipid deposition in this area.…”

“…One potential explanation for the lack of benefit in these trials is that renal ischemia causes irreversible atherogenic changes and that restoration of renal blood flow has no effect on mitigating the damage to the vasculature 4. Biological plausibility of this hypothesis is provided by numerous studies showing that decreased renal perfusion is associated with RAS activation,5 and data from animal models showing that even short‐term elevation in angiotensin II (Ang‐II) levels can accelerate the development of atherosclerosis and lead to changes in the arterial wall that persist even after Ang‐II levels return to baseline 6, 7, 8, 9, 10, 11. In addition, RAS has been shown to result in elevated oxidative stress, sympathoadrenergic activation, and impaired vasoactive responses, both within the kidney and the systemic microcirculation 12, 13…”

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

“…In the present study, aliskiren attenuated the intense pro-inflammatory profile in retina of Ren-2 rats with diabetes or OIR, with a reduction in leucostasis, ICAM-1 production and ED-1 immunolabelling to control levels. There is evidence that aliskiren reduced the macrophage content of atherosclerotic plaques [30], leucocyte adhesion in femoral arteries [31] and the number of CD11b + and CD11c + antigen presenting cells in a model of multiple sclerosis [32]. The results of the present study are consistent with these findings, and highlight the potent anti-inflammatory properties of aliskiren.…”