Bocan T M, Rosebury W S, Mueller S B, Kuchera S, Welch K, Daugherty A, Cornicelli J A
Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, MI 48105, USA.
Atherosclerosis. 1998 Feb;136(2):203-16. doi: 10.1016/s0021-9150(97)00204-9.
Oxidant signalling and lipoprotein oxidation may play important roles in atherosclerotic lesion development. Given coincident localization of 15-lipoxygenase (15-LO), stereospecific products of 15-LO and epitopes of modified LDL in atherosclerotic lesions, we hypothesized that inhibition of 15-LO by PD146176, an inhibitor of 15-LO with an IC50 in cells or isolated enzyme of 0.5-0.8 microM, may limit atherosclerotic lesion development through regulation of monocyte-macrophage enrichment. Rabbits exposed to chronic endothelial denudation of the iliac-femoral artery were meal-fed a 0.25% cholesterol (C), 3% peanut oil (PNO), 3% coconut oil (CNO) diet twice daily with and without 175 mg/kg PD146176 for 12 weeks. In a second study, atherosclerotic lesions were pre-established in rabbits through chronic endothelial denudation and meal-fed a 0.5% C, 3% PNO, 3% CNO diet for 9 weeks and a 0% C/fat diet for 6 weeks prior to an 8 week administration of PD146176 at 175 mg/kg, q.d. Plasma total and lipoprotein cholesterol exposure were similar in control and PD146176-treated animals in both studies but PD146176 increased plasma triglyceride exposure 2- to 4-fold. Plasma PD146176 concentrations ranged from 99 to 214 ng/ml at 2 h post-dose. In the progression study, the iliac-femoral monocyte-macrophage area was reduced 71%, cross-sectional lesion area was unchanged and cholesteryl ester (CE) content was reduced 63%. In the regression study, size and macrophage content of iliac-femoral, fibrous plaque-like lesions were decreased 34%, CE content was reduced 19% and gross extent of thoracic aortic lesions were reduced 41%. We conclude that PD146176 can limit monocyte macrophage enrichment of atherosclerotic lesions and can attenuate development of fibrofoamy and fibrous plaque lesions in the absence of changes in plasma total or lipoprotein cholesterol concentrations.
氧化应激信号传导和脂蛋白氧化可能在动脉粥样硬化病变发展中起重要作用。鉴于15-脂氧合酶（15-LO）、15-LO的立体特异性产物以及修饰低密度脂蛋白（LDL）的表位在动脉粥样硬化病变中的共定位，我们推测，IC50在细胞或分离酶中为0.5 - 0.8微摩尔的15-LO抑制剂PD146176可能通过调节单核细胞 - 巨噬细胞富集来限制动脉粥样硬化病变发展。对暴露于髂股动脉慢性内皮剥脱的兔子，每天分两次喂食含0.25%胆固醇（C）、3%花生油（PNO）、3%椰子油（CNO）的饮食，同时给予或不给予175毫克/千克的PD146176，持续12周。在第二项研究中，通过慢性内皮剥脱在兔子中预先建立动脉粥样硬化病变，先喂食含0.5% C、3% PNO、3% CNO的饮食9周，然后在给予175毫克/千克的PD146176，每日一次，持续8周之前，喂食不含胆固醇/脂肪的饮食6周。在两项研究中，对照动物和接受PD146176治疗的动物的血浆总胆固醇和脂蛋白胆固醇暴露情况相似，但PD146176使血浆甘油三酯暴露增加了2至4倍。给药后2小时，血浆PD146176浓度范围为99至214纳克/毫升。在进展研究中，髂股单核细胞 - 巨噬细胞区域减少了71%，横截面病变面积未改变，胆固醇酯（CE）含量减少了63%。在消退研究中，髂股纤维斑块样病变的大小和巨噬细胞含量减少了34%，CE含量减少了19%，胸主动脉病变的总体范围减少了41%。我们得出结论，在血浆总胆固醇或脂蛋白胆固醇浓度无变化的情况下，PD146176可以限制动脉粥样硬化病变中单核细胞巨噬细胞的富集，并可以减轻纤维泡沫和纤维斑块病变的发展。
