Impairment of endothelium-dependent arterial relaxation by high-fat feeding in ApoE-deficient mice - Toward normalization by human ApoA-I expression

Background-Atherogenic lipoproteins can impair the endothelium-dependent ar terial relaxation, and circumstantial evidence suggests a beneficial role o f plasma high density lipoproteins and apolipoprotein (apo) A-I in countera cting the endothelium dysfunction. In the present study, vascular reactivit y was determined in control, apoE-deficient mice (apoE-KO mice), and apoE-d eficient mice expressing human apoA-I (apoE-KO/HuAITg mice). Methods and Results-In the first part of the study, control and apoE-KO mic e were fed a low-fat or a high-fat diet for 23 weeks, and the vasoactive re sponses of isolated thoracic aortic segments to norepinephrine, sodium nitr oprusside, 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 pr oduced a significant 3-fold increase in the mean concentration required to produce a half-maximal relaxing effect (EC50) of ACh as compared with contr ol mice. This reflects a weaker sensitivity to ACh of the aortic segments f rom the apoE-deficient animals. In the second part of the study, the mean E C50 for ACh after high-fat feeding was found to be 4.4-fold lower in apoE-K O/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 i s improved by the expression of human apoA-I. Conclusions-The present study demonstrates that the endothelium-dependent a rterial relaxation is impaired in apoE-KO mice fed the high-fat diet. The e ndothelium dysfunction tends to be normalized by human apoA-I expression.