Elsevier

Atherosclerosis

Volume 215, Issue 2, April 2011, Pages 301-308
Atherosclerosis

Oral exposure to acrolein exacerbates atherosclerosis in apoE-null mice

https://doi.org/10.1016/j.atherosclerosis.2011.01.001Get rights and content

Abstract

Background

Acrolein is a dietary aldehyde that is present in high concentrations in alcoholic beverages and foods including cheese, donuts and coffee. It is also abundant in tobacco smoke, automobile exhaust and industrial waste and is generated in vivo during inflammation and oxidative stress.

Objectives

The goal of this study was to examine the effects of dietary acrolein on atherosclerosis.

Methods

Eight-week-old male apoE-null mice were gavage-fed acrolein (2.5 mg/kg/day) for 8 weeks. Atherosclerotic lesion formation and composition and plasma lipids and platelet factor 4 (PF4) levels were measured. Effects of acrolein and PF4 on endothelial cell function was measured in vitro.

Results

Acrolein feeding increased the concentration of cholesterol in the plasma. NMR analysis of the lipoproteins showed that acrolein feeding increased the abundance of small and medium VLDL particles. Acrolein feeding also increased atherosclerotic lesion formation in the aortic valve and the aortic arch. Immunohistochemical analysis showed increased macrophage accumulation in the lesions of acrolein-fed mice. Plasma PF4 levels and accumulation of PF4 in atherosclerotic lesions was increased in the acrolein-fed mice. Incubation of endothelial cells with the plasma of acrolein-fed mice augmented transmigration of monocytic cells, which was abolished by anti-PF4 antibody treatment.

Conclusions

Dietary exposure to acrolein exacerbates atherosclerosis in apoE-null mice. Consumption of foods and beverages rich in unsaturated aldehydes such as acrolein may be a contributing factor to the progression of atherosclerotic lesions.

Introduction

The formation and progression of atherosclerotic lesions are affected by multiple genetic and environmental factors. Extensive work has shown that a high caloric intake and consumption of diets rich in saturated fatty acids accelerate atherogenesis; however, the effects of individual food components are less well understood. Human diet is a complex mixture of several constituents and contains reactive chemicals that have the potential to affect cardiovascular health and function. Of these, the consumption of aldehydes may be particularly significant. Aldehydes are highly reactive chemicals that are present in high abundance in most sources of food and water. More than 300 different aldehydes (e.g., crotonaldehyde, furfural, formaldehyde, and acetaldehyde) have been identified in different food substances [1], [2]. High concentrations of the unsaturated aldehydes such as acrolein are present in alcoholic beverages and foods including cheese, donuts and coffee [1]. The unsaturated aldehyde hexenal is used as a common flavoring agent. Heating and cooking of fats, oils and sugar also generate high concentrations of aldehydes [3]. Heating decreases the cis-double bond content of triglycerides and increases the formation of trans-unsaturated aldehydes such as acrolein [3]. Aldehydes are also present in drinking water. Storage of carbonated or non-carbonated water in plastic bottles also generates a variety of aldehydes [4]. At least 36 different aldehydes have been identified in water of which acrolein and endrin aldehyde are the two highest priority pollutants [5]. The recommended maximum concentration of acrolein in water is 65 μg/l, however these limits are often exceeded [5]. The overall daily human consumption of total aldehydes is estimated to be approximately 7 mg/kg of which about 5 mg/kg is unsaturated aldehydes [5], [6]. Nevertheless, the cardiovascular toxicity of dietary aldehydes remains poorly understood.

We have shown that in vitro acrolein evokes delayed vasorelaxation of rat aortic rings, whereas acrolein exposure in vivo compromises vessel contractility [7]. We also observed that acute exposure to acrolein induces vasodilation of the mesenteric bed in rats and mice [8]. Others have shown that in vitro acrolein is cytotoxic to endothelial cells [9]. In addition, our studies show that oral exposure to acrolein in mice increases the sensitivity of the heart to ischemia-reperfusion injury and abolishes the protective effects of the late phase of ischemic preconditioning [6]. Moreover, recent studies have also reported that oral exposure to acrolein induces hyperlipidemia in mice [5] and activates matrix metalloproteinases (MMPs) by increasing the formation of free radicals in macrophages [10]. However, the effects of dietary acrolein on atherogenesis have not been studied. Accordingly, the current study was designed to investigate whether oral exposure to acrolein, as a model of dietary ingestion of unsaturated aldehydes, affects atherosclerotic lesion formation in mice. Results of this study show that chronic oral exposure to acrolein increases the plasma concentration of cholesterol and the chemokine platelet factor 4 (PF4), and exacerbates the formation of atherosclerotic lesions.

Section snippets

Housing and treatment of mice

Male apoE−/− mice (B6.129P2-Apoetm1Unc/J) were obtained from Jax Labs, Bar Harbor, ME. Mice were housed under pathogen-free conditions in the University of Louisville vivarium under controlled temperature and 12 h light/12 h dark cycle. Mice were maintained on a standard chow diet (PicoLab Rodent Chow 20 containing 4.5% fat by weight and 0.02% cholesterol). Starting at eight weeks of age mice were fed acrolein (2.5 mg/kg/day; n = 11) or tap water (vehicle; controls; n = 14) daily by gavage for 8

Exposure to acrolein causes hypercholesterolemia

To examine whether chronic exposure to acrolein affects the concentrations of plasma lipoproteins, we measured total cholesterol and triglycerides concentration in the plasma of acrolein-fed apoE-null mice. As shown in Table 1, exposure to acrolein significantly increased plasma cholesterol levels (P < 0.05). A modest increase was also observed in the plasma triglyceride concentration of acrolein-fed mice, but it was not statistically significant. NMR analysis of plasma lipoproteins showed that

Discussion

Atherosclerosis is a complex and multi-factorial disease. Interplay of multiple factors including hyperlipidemia, endothelial activation, monocyte recruitment and their differentiation into macrophages, foam cell formation and activation of platelets is well documented in the pathogenesis of atherosclerosis. In the present study, we show that exposure to a dietary and environmental aldehyde, acrolein, exacerbates atherosclerotic lesion formation in mice. This outcome is likely because exposure

Conflict of interests

None declared.

Acknowledgements

The authors thank Mr. David Young and Ms. Barbara Bishop for expert technical assistance. This work was supported in part by NIH grants ES17260, ES11594, ES11860, HL55477, HL59378, HL89380 and RR 24489.

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