Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols
Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols
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DOI：
10.1161/atvbaha.117.310244
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发表时间：
2018-04-01
影响因子：
8.7
通讯作者：
Egashira, Kensuke
中科院分区：
文献类型：
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作者：
Honda, Katsuya;Matoba, Tetsuya;Egashira, Kensuke
目的在他汀类药物时代，斑块侵蚀作为急性冠状动脉综合征发病机制之一的重要性日益增加。然而，目前使用的降脂药在预防与斑块糜烂相关的血栓性并发症中的临床疗效尚未明确。因此，我们研究了依折麦布或瑞舒伐他汀单药治疗对自发性动脉粥样硬化血栓闭塞症的治疗效果。方法和结果日本白色兔，喂养高胆固醇饮食，股动脉损伤的球囊导管，然后血管紧张素II连续给药。在94%的这些动脉中，在球囊损伤5周（中位数）后观察到自发性血栓闭塞。组织化学分析表明，损伤的动脉具有与人类斑块糜烂相似的病理学特征：（1）自发性血栓闭塞，（2）缺乏内皮细胞，（3）血管平滑肌细胞中组织因子表达。依折麦布（1.0 mg/kg/天）而非瑞舒伐他汀（0.6 mg/kg/天）显著降低了动脉血栓性闭塞，伴再内皮化加速和血清氧化固醇降低，尽管治疗期间血清胆固醇水平相当。7-酮胆固醇抑制人脐静脉内皮细胞的迁移。7-酮基胆固醇和27-羟基胆固醇均增加培养的大鼠血管平滑肌细胞中组织因子的表达。组织因子的表达也诱导血清从车辆或瑞舒伐他汀治疗的兔子，但诱导衰减与依折麦布治疗rabbits.Conclusions的血清，我们已经建立了一种新的兔模型，自发性动脉粥样硬化闭塞斑块破裂，是可行的测试各种药物治疗的治疗效果。依折麦布可通过降低血清氧化固醇来减少浅表斑块糜烂后的动脉粥样硬化血栓形成并发症。
Objective Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion.Approach and Results Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits.Conclusions We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols.