Journal Article

Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI

Herta M. Crauwels, Cor E. Van Hove, Paul Holvoet, Arnold G. Herman and Hidde Bult

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 59, issue 1, pages 189-199
Published in print July 2003 | ISSN: 0008-6363
Published online July 2003 | e-ISSN: 1755-3245 | DOI: http://dx.doi.org/10.1016/S0008-6363(03)00353-5
Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI

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Abstract

Objective: Apolipoprotein E-deficient mice (apoE−/−) on a regular diet become hypercholesterolemic and develop atherosclerosis, but endothelium-dependent relaxation remains undisturbed for up to 6 months. We investigated whether vasomotor dysfunction develops in aged apoE−/−, whether the defect was systemic (hypercholesterolemia-dependent) or focal (plaque-related), and the effect of human apolipoprotein AI transgenesis (apoAI/E−/−). Methods: Arteries of apoE−/− (n = 5), apoAI/E−/− (n = 6) and C57Bl/6J (WT, n = 4) mice (18 months) were systematically dissected for isometric tension recording and subsequent morphometry. Results: Acetylcholine (ACh)-induced relaxation was impaired (P<0.01) in atherosclerotic segments of apoE−/− (26±14%) as compared to WT mice (93±2%). Similar reduced (P<0.01) responses to adenosine 5′-triphosphate (apoE−/− 38±14, WT 94±3%) and the calcium ionophore A23187 (apoE−/− 19±6%, WT 97±2%) pointed to a post-receptor defect. Indeed, responses to exogenous nitric oxide were impaired in atherosclerotic segments as well (apoE−/− 71±7%, WT 92±1%, P<0.05). Furthermore, relaxations inversely correlated with plaque size (ACh rs=−0.74, P<0.01). In adjacent plaque-free segments however, responses to ACh (apoE−/− 92±3%, WT 97±1%) and all other agents were preserved, despite the prolonged hypercholesterolemia. ApoAI improved vasomotor responses in atherosclerotic segments. However, negative correlations between maximal relaxation and plaque area remained in apoAI/E−/− mice (ACh rs=−0.67, P<0.01). Indeed, covariate analysis of variance did not point to direct protection of vasomotor function by apoAI when the smaller lesions were taken into account. Conclusions: Endothelial dysfunction in apoE−/− mice is not affected by hypercholesterolemia alone, but is strictly associated with plaque formation. Human apoAI transgenesis—known to raise HDL—attenuated atherogenesis, thereby indirectly improving relaxation responses in apoE−/− mice.

Keywords: Atherosclerosis; Nitric oxide; Endothelial function; Vasodilation; Histopathology; Hypercholesterolemia; apoAI; HDL

Journal Article.  5150 words.  Illustrated.

Subjects: Cardiovascular Medicine

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