Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Br J Pharmacol. 2009 Dec;158(8):1951-60. doi: 10.1111/j.1476-5381.2009.00470.x.
The risk for cardiovascular events including venous and arterial disease and stroke is elevated after treatment with estrogen and medroxyprogesterone acetate (MPA) in postmenopausal women. Here, we have investigated the effect of MPA on arterial thrombosis and atherosclerosis in a murine model of atherosclerosis.
Apolipoprotein E (ApoE)-/- mice were bilaterally ovariectomized and treated with placebo, MPA (27.7 microg day(-1)) and MPA + 17-beta-oestradiol (E2; 1.1 microg day(-1)) for 90 days, on a Western-type diet. Thrombotic response was measured in a photothrombosis model, platelet activation by fluorescence activated cell sorting (FACS) analysis (CD62P) and thrombin generation by the endogenous thrombin potential (ETP). Furthermore, aortic plaque burden and aortic root plaque composition were determined.
MPA and MPA + E2-treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for alpha-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2.
Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis.
在绝经后女性中，雌激素和醋酸甲羟孕酮（MPA）治疗会增加心血管事件（包括静脉和动脉疾病以及中风）的风险。在这里，我们研究了 MPA 对动脉血栓形成和动脉粥样硬化的影响，使用了动脉粥样硬化的小鼠模型。
载脂蛋白 E（ApoE）-/- 小鼠双侧卵巢切除术，并用安慰剂、MPA（27.7μg/天）和 MPA+17-β-雌二醇（E2；1.1μg/天）处理 90 天，采用西方饮食。通过光血栓形成模型测量血栓反应，通过荧光激活细胞分选（FACS）分析（CD62P）测量血小板活化，通过内源性凝血酶潜力（ETP）测量凝血酶生成。此外，还测定了主动脉斑块负担和主动脉根部斑块组成。
MPA 和 MPA+E2 处理的动物表现出加重的血栓反应，表现为稳定闭塞的时间显著缩短。MPA 的促血栓形成作用与 ETP 增加平行，而血小板活化不受影响。此外，MPA+E2 减少了斑块基质中α-平滑肌肌动蛋白阳性细胞的数量，并增加了透明质酸。有趣的是，MPA 减少了总斑块负担，但 MPA+E2 没有改变。
尽管 MPA 对 ApoE 缺陷型小鼠的动脉粥样硬化有抑制作用，但长期使用 MPA 和 MPA+E2 会增加动脉血栓形成。增加的凝血酶形成、平滑肌含量减少和非胶原蛋白斑块基质的重塑可能与促血栓形成作用有关。因此，MPA 对动脉血栓形成和动脉粥样硬化有不同的作用。
