Gallaugher Laura D, Henry Jon C, Kearns Patrick N, Elford Howard L, Bergdall Valerie K, Cardounel Arturo J
Division of University Laboratory Animal Resources and the Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Comp Med. 2009 Dec;59(6):567-72.
Atheroproliferative disorders such as atherosclerosis are an important health problem and one of the leading causes of morbidity and mortality in the United States. Minimally invasive therapeutic procedures, including angioplasty with stent deployment, are used frequently for obstructive coronary artery disease. However, restenosis, a proliferative vascular response, is a common sequela to this procedure. The current study investigated the effect of inhibiting ribonucleotide reductase (RR), an enzyme necessary for cellular proliferation, in an attempt to ameliorate the proliferative response. Two RR inhibitors, didox and hydroxyurea, were chosen for their potent antiproliferative properties. Studies were carried out by using a double-injury rabbit model, in which endothelial denudation was followed by the administration of a high-fat diet. At 4 wk after initial endothelial denudation, the developing atherosclerotic lesion was subjected to transluminal balloon dilation to simulate clinical intervention with percutaneous transluminal angioplasty. The degree of restenosis and atheroproliferation was assessed at 8 wk. Histologic evaluation of the lesion demonstrated that treatment with didox and hydroxyurea significantly decreased lesion area and lumen loss. These results suggest that RR inhibition may be an effective new tool for the treatment of atheroproliferative disorders.
动脉粥样硬化等动脉粥样增生性疾病是一个重要的健康问题,也是美国发病和死亡的主要原因之一。包括血管成形术并植入支架在内的微创治疗程序常用于治疗阻塞性冠状动脉疾病。然而,再狭窄是一种血管增殖反应,是该治疗程序常见的后遗症。当前的研究调查了抑制核糖核苷酸还原酶(RR)(一种细胞增殖所必需的酶)的效果,以试图改善增殖反应。选择了两种RR抑制剂——双吖啶和羟基脲,因其具有强大的抗增殖特性。研究采用双损伤兔模型进行,先进行内皮剥脱,随后给予高脂饮食。在初次内皮剥脱后4周,对正在形成的动脉粥样硬化病变进行腔内球囊扩张,以模拟经皮腔内血管成形术的临床干预。在8周时评估再狭窄和动脉粥样增生的程度。对病变的组织学评估表明,双吖啶和羟基脲治疗显著减少了病变面积和管腔狭窄。这些结果表明,抑制RR可能是治疗动脉粥样增生性疾病的一种有效的新方法。