Transiently heightened angiotensin II has distinct effects on atherosclerosis and aneurysm formation in hyperlipidemic mice
Introduction
Angiotensin II (AngII) has been widely accepted as a pivotal mediator of tissue destruction in hypertension-induced arteriosclerosis as well as vascular and tissue remodeling that follows cardiac and renal injuries. Epidemiologic studies find that inhibition of AngII actions is associated with fewer cardiovascular events and less mortality [1], [2], [3]. Animal studies further support a direct role of AngII in vasculopathy, including atherosclerosis and aneurysm formation [1], [4], [5], [6], [7], [8], [9], [10]. However, while AngII is recognized to potentiate vasculopathy, all the studies to date have examined these effects at the end of a continuous exposure to heightened AngII levels. There is no information related to the consequences of the potentially more relevant short-term elevations in AngII activity that prevail in clinical settings. Transient elevations in AngII may be harmful, with delayed consequences occurring long after AngII-induced hemodynamic effects that are related to changes in chemokine/cytokine stimulation and cellular phenotype. Indeed, short-term and/or repeated exposures to elevated AngII has been noted to amplify vascular pathology linked to subsequent hypertension [11]. Clinically, transient stimulation of AngII during episodes of systemic hypotension, volume depletion, cardiac ischemia occur on the background of prevailing risk factors for atherosclerotic heart disease including hyperlipidemia, hypertension, diabetes and renal dysfunction and may predispose to further cardiovascular pathology. Notably, diuretic treatment which is a mainstay therapeutic intervention in patients with hypertension, cardiac and renal insufficiency is a common cause of AngII stimulation and may, in some circumstances, potentiate cardiovascular disease. This issue is especially timely in view of the recent recommendations that diuretics should be the initial therapy for hypertension [12]. The possibility that even transient elevations in AngII may be detrimental also raises the possibility that the long-term benefits of AngII antagonism are, at least in part, dependent on the completeness of AngII antagonism that is independent of effects on systemic blood pressure [13]. In these studies, we examined whether transient elevation of AngII can effect initiation, progression and vascular remodeling that contribute to long-term vascular pathology including atherosclerosis and aneurysms.
Section snippets
Mice
Female apolipoprotein E-deficient (apoE−/−) mice on C57BL/6 background were obtained from Jackson Laboratories. All mice were maintained on a normal mouse chow diet (RP5015; PMI Feeds Inc.). Animal care and the experimental procedures were carried out in accordance with National Institutes of Health and Vanderbilt University animal care facility guidelines.
Experimental protocol
Alzet osmotic minipumps (model 1002; Durect Corporation) were implanted subcutaneously in 8-week-old apoE−/− mice under isoflurane
Whole animal studies
Body weight prior to AngII/saline-infusion was comparable and increased similarly over the length of the study. Before any treatment, AngII-1000 weighed 16.6 ± 0.2 g versus saline at 16.3 ± 0.2 g (p = NS). Two weeks later, the weights remained similar: 18.3 ± 0.3 g (n = 66) versus 18.0 ± 0.3 g (n = 24) (p = NS) and at 24 weeks, the weights was nearly identical (24.6 ± 0.3 g, n = 18 versus 24.5 ± 0.9 g, n = 12, p = NS). Similarly, serum lipids were not affected by exposure to AngII: the cholesterol in AngII-infused mice was
Discussion
These studies make the novel observations that transient increase in AngII amplifies development of atherosclerosis in the long-term, and causes prompt but reversible aneurysms. Thus, 2 weeks of heightened AngII in 8-week-old apoE-deficient mice caused one and a half-fold greater atherosclerotic lesions in the proximal aorta and more than three-fold greater atherosclerotic lesions in the distal aorta 14 weeks after the exposure. Whereas recent studies have noted the deleterious effect of
Acknowledgment
This work was supported in part by grants from NIH DK44757 (V.K.), DK37868 (I.I.), HL 53989 (M.F.L), HL 65709 and 57986 (S.F.). The Lipid, Lipoprotein and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotyping Center (NIH DK59637-01).
There are no conflict of interest disclosures pertaining to this work.
References (33)
- et al.
Dual renin-angiotensin system blockade at optimal doses for proteinuria
Kidney Int.
(2002) - et al.
Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice
Mol Cell
(1998) - et al.
Cytokine expression in respiratory syncytial virus-infected mice as measured by quantitative reverse-transcriptase PCR
J Virol Methods
(2003) Theodore cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis
Hypertension
(2001)- et al.
Collaborative Study Group: renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes
N Engl J Med
(2001) Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients
New Engl J Med
(2000)- et al.
Chronic angiotensin II infusion promotes atherogenesis in low density lipoprotein receptor −/− mice
Ann N Y Acad Sci
(1999) - et al.
Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized LDL: a possible role for interleukin-6
Arterioscler Thromb Vasc Biol
(2001) - et al.
Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice
Circulation
(2001) - et al.
Acceleration of atherosclerotic lesions in transgenic mice with hypertension by the activated renin-angiotensin system
Lab Invest
(1997)