Elsevier

Atherosclerosis

Volume 178, Issue 1, January 2005, Pages 9-17
Atherosclerosis

Enalapril attenuates angiotensin II-induced atherosclerosis and vascular inflammation

https://doi.org/10.1016/j.atherosclerosis.2004.08.023Get rights and content

Abstract

Angiotensin converting enzyme (ACE) inhibitors prevent a wide variety of key events underlying atherogenesis. Whether these actions depend solely on reduction of angiotensin II (Ang II) generation is still to be determined. This study was undertaken to determine whether enalapril, an ACE inhibitor, prevents atherosclerosis and vascular inflammation induced by Ang II in apolipoprotein E-deficient (apoE-KO) mice. Subcutaneous infusion of Ang II (1.44 mg/(kg day)) for 4 weeks increased blood pressure and accelerated atherosclerosis development in the carotid arteries. The expression of the endothelial adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as the chemokines monocyte chemotactic protein-1 (MCP-1) and macrophage-colony stimulating factor (M-CSF) was up-regulated in the aortas of Ang II-treated mice. Enalapril co-treatment (25 mg/(kg day), in drinking water) prevented the development of atherosclerosis without affecting blood pressure or circulating cholesterol. In addition to preventing the Ang II-induced over-expression of adhesion molecules and chemokines in the aorta, enalapril up-regulated the expression of peroxisome proliferator-activated receptors (PPARs)-α and -γ, potential anti-inflammatory transcription factors. In the aortic arch, a lesion-prone site, the co-treatment with enalapril reduced the percentage of arterial wall occupied by macrophages and foam cells, medial sclerosis and elastin reduplication. Together, these data suggest an important role for Ang II-independent mechanisms in the antiatherogenic and anti-inflammatory effects of ACE inhibitors.

Introduction

Angiotensin II (Ang II) induces a wide variety of vascular events including endothelial activation [1] and dysfunction [2], cell proliferation [3] and monocyte chemoattraction [4], which play an important role in atherosclerosis development. Induction of macrophage cholesterol biosynthesis [5] and macrophage uptake of modified lipoproteins [6] are additional mechanisms contributing to the atherogenic action of Ang II. The inhibition of Ang II generation could per se explain the antiatherogenic effect of angiotensin converting enzyme (ACE) inhibitors reported by numerous studies [7], [8]. Some studies, however, have revealed that not all the potential antiatherosclerotic actions of ACE inhibitors are shared by the Ang II type 1 (AT1) receptor antagonists, suggesting that mechanisms independent of the inhibition of Ang II generation may also be involved. For instance, Sun et al. [8] observed that the ACE inhibitors captopril and quinapril were more effective than losartan, an AT1 receptor antagonist, in improving vascular function in hypercholesterolemic rabbits. Results by Berkenboo et al. [9] showed that ramipril but not losartan prevented ox-LDL-induced endothelial damage in Watanable hypercholesterolemic rabbits.

The migration and accumulation of monocytes into the subendothelial space of the vessel wall is one of the earliest detectable responses in the formation of atherosclerotic lesions [10]. Expression of adhesion molecules by endothelial cells and local production of chemoattractants are key molecular events for monocyte migration/accumulation [11]. Down-regulation of such chemoattractant mediators and the prevention of tissue macrophage accumulation are recognized as important mechanisms of drugs targeting atherogenesis, including ACE inhibitors [12], [13]. Although previous studies have shown Ang II-independent mechanisms in the actions of ACE inhibitors on endothelial function [8] and LDL susceptibility to oxidation [9] accompanying atherosclerosis, there is no direct evidence that such alternative mechanisms account for their antiatherogenic and anti-inflammatory actions. Therefore, the present study aimed at determining whether enalapril, an ACE inhibitor, prevents atherosclerosis and vascular inflammation induced by Ang II in apolipoprotein E-deficient (apoE-KO) mice. Because infiltrating monocytes/macrophages may also play a role in the Ang II-induced aortic aneurysm in apoE-KO mice [14], [15], this study also evaluated the efficacy of enalapril treatment on this process. Our findings provide the first strong evidence for the participation of Ang-II independent mechanisms in the antiaterosclerotic and anti-inflammatory actions of ACE inhibitors.

Section snippets

Animals and experimental design

Six-month-old male apoE-KO mice were obtained from Jackson Laboratories and fed a standard rodent chow. Three groups were studied as follows: (1) untreated controls (control, n = 8); (2) Ang II (Calbiochem, San Diego, CA) infused subcutaneously by implanted minipumps (Alzet, Model 2004; ALZA Corp., Palo Alto, CA) at a dose of 1.44 mg/(kg day) for 4 weeks (Ang II, n = 9); (3) The same dose of Ang II infused for 4 weeks plus enalapril (Sigma, St. Louis, MO) at a dose of 25 mg/(kg day) (Ang II plus

Results

As shown in Table 1, no significant change in body weight and lipid profile was found between the experimental groups. Chronic infusion of Ang II in apoE-KO mice increased blood pressure, which was not affected by enalapril co-treatment (Fig. 1A).

Discussion

The present study demonstrates that the ACE inhibitor, enalapril, prevented atherosclerosis development and attenuated aneurysm formation in apoE-KO mice induced by Ang II, without changing blood pressure or lipid profile. In addition, Ang II-induced over-expression of endothelial-derived adhesion molecules and chemokines as well as subintimal macrophage infiltration were prevented by enalapril treatment. Another striking finding was the ability of enalapril to up-regulate the expression of

Acknowledgment

The technical assistance of Jefferson Davis and the Berlex Biosciences Animal Care group is gratefully appreciated. Supported partially by the BioStar (Biotechnology Strategic Alliance Research) grant.

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