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(Circulation. 1999;100:1230-1235.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Impairment of Endothelium-Dependent Arterial Relaxation By High-Fat Feeding in ApoE-Deficient Mice

Toward Normalization By Human ApoA-I Expression

Valérie Deckert, PhD; Gérard Lizard, PhD; Nicolas Duverger, PhD; Anne Athias, MS; Viviane Palleau, BS; Florence Emmanuel, PhD; Maryvonne Moisant, MS; Philippe Gambert, MD, PhD; Christian Lallemant, MD; Laurent Lagrost, PhD

From the Laboratoire de Biochimie des Lipoprotéines - INSERM U498, Hôpital du Bocage, Dijon (V.D., G.L., A.A., V.P., M.M., P.G., C.L., L.L.), and the Centre de Recherches de Vitry-Alfortville, Rhône-Poulenc Rorer, Gencell Division, Vitry-sur-Seine, France (N.D., F.E.).

Correspondence to Dr Laurent Lagrost, Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Hôpital du Bocage, BP 1542, 21034 Dijon, France. E-mail Laurent.Lagrost{at}u-bourgogne.fr

Background—Atherogenic lipoproteins can impair the endothelium-dependent arterial relaxation, and circumstantial evidence suggests a beneficial role of plasma high density lipoproteins and apolipoprotein (apo) A-I in counteracting the endothelium dysfunction. In the present study, vascular reactivity was determined in control, apoE-deficient mice (apoE-KO mice), and apoE-deficient mice expressing human apoA-I (apoE-KO/HuAITg mice).

Methods and Results—In the first part of the study, control and apoE-KO mice were fed a low-fat or a high-fat diet for 23 weeks, and the vasoactive responses of isolated thoracic aortic segments to norepinephrine, sodium nitroprusside, and acetylcholine (ACh) were determined. Whereas norepinephrine, sodium nitroprusside, and ACh evoked similar vascular responses in control and apoE-KO mice fed the low-fat diet, high-fat feeding in apoE-KO mice produced a significant 3-fold increase in the mean concentration required to produce a half-maximal relaxing effect (EC₅₀) of ACh as compared with control mice. This reflects a weaker sensitivity to ACh of the aortic segments from the apoE-deficient animals. In the second part of the study, the mean EC₅₀ for ACh after high-fat feeding was found to be 4.4-fold lower in apoE-KO/HuAITg mice than in apoE-KO mice, indicating that the reduced sensitivity to ACh of the thoracic aorta from the apoE-KO mice fed the high-fat diet is improved by the expression of human apoA-I.

Conclusions—The present study demonstrates that the endothelium-dependent arterial relaxation is impaired in apoE-KO mice fed the high-fat diet. The endothelium dysfunction tends to be normalized by human apoA-I expression.

Key Words: apolipoproteins • mice • atherosclerosis • vascular reactivity

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