Ou Jingsong, Ou Zhijun, Jones Deron W, Holzhauer Sandra, Hatoum Ossama A, Ackerman Allan W, Weihrauch Dorothee W, Gutterman David D, Guice Karen, Oldham Keith T, Hillery Cheryl A, Pritchard Kirkwood A
Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
Circulation. 2003 May 13;107(18):2337-41. doi: 10.1161/01.CIR.0000070589.61860.A9. Epub 2003 May 5.
Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O2*-) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr-/-) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O2*- generation.
Arterioles were isolated from hypercholesterolemic Ldlr-/- mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O2*- generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr-/- mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O2*- in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice.
These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD. Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases.
高胆固醇血症和镰状细胞病（SCD）通过不同机制损害内皮依赖性血管舒张。高胆固醇血症通过低密度脂蛋白（LDL）依赖性机制损害血管舒张。SCD的特征是一种慢性炎症状态，其中缺血组织中的黄嘌呤氧化酶（XO）增加血管超氧阴离子（O2*-）的生成。最近的报告表明，载脂蛋白（apo）A-1模拟物可抑制喂食西方饮食的低密度脂蛋白受体缺失（Ldlr-/-）小鼠的动脉粥样硬化。在此，我们假设L-4F（一种apoA-1模拟物）通过减少增加O2*-生成的机制来维持高胆固醇血症和SCD中的血管舒张。
从小鼠高胆固醇血症Ldlr-/-小鼠和SCD小鼠中分离出小动脉，这些小鼠分别用生理盐水或L-4F（每天1mg/kg）处理。通过视频显微镜测定对乙酰胆碱的血管舒张反应。通过氢乙锭测定法在动脉段以及通过超氧化物歧化酶抑制的高铁细胞色素c还原在刺激的内皮细胞培养物中测定L-4F对LDL诱导的内皮依赖性O2*-生成增加的影响。通过免疫荧光测定L-4F对与SCD小鼠肺小动脉结合的XO以及肝脏中XO含量的影响。高胆固醇血症损害了Ldlr-/-小鼠的血管舒张，而L-4F显著改善了这种情况。L-4F抑制了动脉段和刺激培养物中LDL诱导的O2*-增加。SCD损害了血管舒张功能，增加了与肺内皮结合的XO，并降低了肝脏XO含量。与未治疗的SCD小鼠相比，L-4F显著改善了血管舒张功能，降低了与肺内皮结合的XO，并增加了肝脏XO含量。
这些数据表明，L-4F可保护高胆固醇血症和SCD中的内皮依赖性血管舒张。我们的研究结果表明，L-4F可在多种疾病模型中恢复血管内皮功能，可能适用于治疗多种血管疾病。
