Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice

Abstract

Background-Angiotensin II may contribute to the development and progression of atherosclerotic lesions because of its growth and proinflammatory effects. We sought to determine whether angiotensin II-induced hypertension would augment and accelerate the development of atherosclerotic lesions in apoE-deficient mice. Methods and Results-Angiotensin II (0.7 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 SC) was administered to apoE-deficient mice via osmotic minipumps. The animals were placed on either standard chow or an atherogenic diet. After 8 weeks, the mean atherosclerotic lesion area in the descending thoracic and abdominal aortas of animals on a standard chow diet was 0.4Ϯ0.1% compared with 5.2Ϯ1.2% in those animals maintained on an atherogenic diet (PϽ0.0001). In angiotensin II-treated animals on standard chow, the mean lesion area was increased to 11.0Ϯ2.3%, which was further increased to 69.9Ϯ9.4% (PϽ0.0001) in angiotensin II-treated animals on an atherogenic diet. Similar findings were obtained when tissues from the ascending aorta were analyzed. At 8 weeks in mice receiving a standard chow diet, angiotensin II dramatically increased the atherosclerotic lesion area by 840Ϯ83 m 2 (PϽ0.0001). Animals on a high-fat diet had a similar marked increase in lesion area in response to angiotensin II (217Ϯ19 m 2 , PϽ0.0001). In contrast, when hypertension was induced with norepinephrine, only a modest effect on the atherosclerotic lesion area was observed. Conclusions-Angiotensin II-induced hypertension specifically increased the development of atherosclerosis in apoE knockout mice. This response was seen in animals receiving either standard chow or an atherogenic diet. These studies demonstrate the profound effect of angiotensin II on the development of atherosclerosis.

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

“…As expected from previous reports [1,16,17], this A-II dose caused mild increases in atherosclerotic lesions in the ascending and descending aortae, as well as aneurysm formation in the suprarenal aorta. Percent-aortic lesion areas for individual mice in each group are shown in Figure 1, along with representative oil red O-stained aortae.…”

“…The establishment of a mouse model for A-II-induced AS in genetically modified hyperlipidemic mice has been a major advance, facilitating mechanistic studies of A-II-induced inflammatory signaling [1,16,17]. Although many studies have employed the C57BL/6J apolipoprotein E-deficient (apo E −/− ) mouse, these mice show rapid AS progression, due to large increases in circulating chylomicrons and VLDL remnants [18].…”

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

“…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…”

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

“…[1][2][3][4] AngII-induced atherosclerosis is characterized by intimal infiltration of leukocytes that become engorged with lipid. In contrast, AngII induction of AAAs is characterized by medial destruction, macrophage infiltration, thrombus formation, and vascular remodeling.…”