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

doi:10.1016/S0008-6363(03)00353-5

Cardiovascular Research 2003 59(1):189-199; doi:10.1016/S0008-6363(03)00353-5
© 2003 by European Society of Cardiology

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

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

^aDivision of Pharmacology (T2), University of Antwerp (UIA), Universiteitsplein 1, B-2610 Wilrijk, Belgium
^bCentre for Experimental Surgery and Anaesthesiology, University of Leuven (KUL), Leuven, Belgium

herta.crauwels{at}ua.ac.be

^* Corresponding author. Tel.: +32-3-820-2737; fax: +32-3-820-2567.

Objective: Apolipoprotein E-deficient mice (apoE^–/–)on a regular diet become hypercholesterolemic and develop atherosclerosis,but endothelium-dependent relaxation remains undisturbed forup to 6 months. We investigated whether vasomotor dysfunctiondevelops in aged apoE^–/–, whether the defect wassystemic (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 systematicallydissected 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%). Similarreduced (P<0.01) responses to adenosine 5'-triphosphate (apoE^–/–38±14, WT 94±3%) and the calcium ionophore A23187 [GenBank] (apoE^–/– 19±6%, WT 97±2%) pointedto a post-receptor defect. Indeed, responses to exogenous nitricoxide were impaired in atherosclerotic segments as well (apoE^–/–71±7%, WT 92±1%, P<0.05). Furthermore, relaxationsinversely correlated with plaque size (ACh r_s=–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 vasomotorresponses in atherosclerotic segments. However, negative correlationsbetween maximal relaxation and plaque area remained in apoAI/E^–/–mice (ACh r_s=–0.67, P<0.01). Indeed, covariate analysisof variance did not point to direct protection of vasomotorfunction by apoAI when the smaller lesions were taken into account.Conclusions: Endothelial dysfunction in apoE^–/–mice is not affected by hypercholesterolemia alone, but is strictlyassociated with plaque formation. Human apoAI transgenesis—knownto raise HDL—attenuated atherogenesis, thereby indirectlyimproving relaxation responses in apoE^–/– mice.

KEYWORDS Atherosclerosis; Nitric oxide; Endothelial function; Vasodilation; Histopathology; Hypercholesterolemia; apoAI; HDL

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