Cetinkaya Demir Bilge, Uyar Yıldız, Ozbilgin Kemal, Köse Can
Department of Obstetrics and Gynecology, Faculty of Medicine, Uludag University, Bursa, Turkey.
J Obstet Gynaecol Res. 2013 Jan;39(1):229-36. doi: 10.1111/j.1447-0756.2012.01969.x. Epub 2012 Jul 29.
The goal of this study was to investigate the combined effects of raloxifene and atorvastatin in aged ovariectomized rats during endothelial dysfunction and atherosclerotic process.
This study was conducted on 28 Wistar albino female rats randomly divided into four groups. All groups were ovariectomized and one group was kept as the control group (OVX). For four weeks, the remaining three groups were treated with the statin atorvastatin (OVX+AV), the selective estrogen receptor modulator raloxifene (OVX+RL), and both atorvastatin and raloxifene (OVX+RL+AV), respectively. At the end of the treatment period, all rats were sacrificed and thoracic aortas excised, and endothelial cells were immunohistochemically stained for markers in the atherosclerotic process, such as inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α).
Compared to the ovariectomized group, the iNOS level was significantly increased in the OVX+RL group (P=0.002), but contrarily decreased in the groups OVX+AV (P=0.002) and OVX+RL+AV (P=0.002). eNOS levels in the groups OVX+AV (P=0.002) and OVX+RL+AV (P=0.002) were significantly lower than that in the OVX group. When compared to the OVX group, significant reductions in ET-1 and TNF-α levels were found in all treatment groups. A significant decrement in MCP-1 level was found in the OVX+AV group (P=0.002).
In aged ovariectomized rats, the administration of both raloxifene and atorvastatin significantly decreased the levels of ET-1 and TNF-α on endothelial cells. Combined treatment with these drugs shortly after menopause might play a potential preventive role in the early stages of atherosclerosis development.
本研究旨在探讨雷洛昔芬和阿托伐他汀联合应用对老年去卵巢大鼠内皮功能障碍和动脉粥样硬化进程的综合影响。
本研究以28只Wistar白化雌性大鼠为实验对象，随机分为四组。所有组均进行去卵巢手术，其中一组作为对照组（OVX）。在接下来的四周里，其余三组分别接受他汀类药物阿托伐他汀（OVX+AV）、选择性雌激素受体调节剂雷洛昔芬（OVX+RL）以及阿托伐他汀和雷洛昔芬联合用药（OVX+RL+AV）的治疗。治疗期结束后，处死所有大鼠并切除胸主动脉，对内皮细胞进行免疫组织化学染色，检测动脉粥样硬化进程中的标志物，如诱导型一氧化氮合酶（iNOS）、内皮型一氧化氮合酶（eNOS）、内皮素-1（ET-1）、单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子α（TNF-α）。
与去卵巢组相比，OVX+RL组的iNOS水平显著升高（P=0.002），而OVX+AV组（P=0.002）和OVX+RL+AV组（P=0.002）的iNOS水平则相反，呈下降趋势。OVX+AV组（P=0.002）和OVX+RL+AV组（P=0.002）的eNOS水平显著低于OVX组。与OVX组相比，所有治疗组的ET-1和TNF-α水平均显著降低。OVX+AV组的MCP-1水平显著降低（P=0.002）。
在老年去卵巢大鼠中，雷洛昔芬和阿托伐他汀联合给药可显著降低内皮细胞中ET-1和TNF-α的水平。绝经后短期内联合使用这些药物可能在动脉粥样硬化发展的早期阶段发挥潜在的预防作用。
