Statins Promote the Growth of Experimentally Induced Cerebral Aneurysms in Estrogen-Deficient Rats
Statins Promote the Growth of Experimentally Induced Cerebral Aneurysms in Estrogen-Deficient Rats
复制标题
DOI：
10.1161/strokeaha.110.608034
复制
发表时间：
2011-08-01
期刊：
影响因子：
8.3
通讯作者：
Nagahiro, Shinji
中科院分区：
文献类型：
--
作者：
Tada, Yoshiteru;Kitazato, Keiko T.;Nagahiro, Shinji
背景和目的：脑动脉瘤的发病机制与炎症、细胞外基质降解和血管壁细胞凋亡有关。他汀类药物对血管系统具有多效性，与其降胆固醇特性无关。为了探讨脑动脉瘤的详细发病机制，我们在大鼠模型上检测了它们的进展情况，并研究了他汀类药物是否能阻止它们的起始和生长。方法-在高血压、血流动力学应激增加和雌激素缺乏的情况下，建立雌性大鼠脑动脉瘤模型。在腐蚀模型上对动脉瘤的发展进行了形态学评估。观察普伐他汀(5、25、50 mg/kg/d)和辛伐他汀(5 mg/kg/d)对动脉瘤的影响。结果普伐他汀(5 mg/kg/d)可减轻血管内皮细胞损伤，抑制动脉瘤形成，并与内皮型一氧化氮合酶(ENOS)水平升高和人脑内皮细胞黏附分子减少有关。普伐他汀25 mg/(kg·d)、50 mg/(kg·d)和辛伐他汀5 mg/(kg·d)促进动脉瘤生长，大剂量普伐他汀可诱导动脉瘤破裂。他汀类药物的不良作用与细胞凋亡caspase-3水平和末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)阳性细胞数增加有关，提示他汀类药物具有双向作用。结论：本研究首次证实了他汀类药物对脑动脉瘤的生长与细胞凋亡有关，并提出了他汀类药物对脑动脉瘤发生双向作用的警告。进一步的深入研究是必要的，以更好地了解其机制，并确定服用他汀类药物可能会引起有害影响的患者。(笔划。2011；42：2286-2293。)
Background and Purpose-The pathogenesis of cerebral aneurysms is linked to inflammation, degradation of the extracellular matrix, and vascular wall apoptosis. Statins exert pleiotropic effects on the vasculature, independent of their cholesterol-lowering properties. To explore the detailed pathogenesis of cerebral aneurysms, we examined their progression in a rat model and studied whether statins prevent their initiation and growth.Methods-Cerebral aneurysms were induced in female rats subjected to hypertension, increased hemodynamic stress, and estrogen deficiency. The development of aneurysm was assessed morphologically on corrosion casts. The effects of pravastatin (5, 25, or 50 mg/kg per day) and of simvastatin (5 mg/kg per day) on their aneurysms were studied. Human brain endothelial cells were also used to determine the effects of pravastatin.Results-Pravastatin (5 mg/kg per day) reduced endothelial damage and inhibited aneurysm formation; there was an association with increased endothelial nitric oxide synthase (eNOS) levels and a decrease in human brain endothelial cell adhesion molecules. Unexpectedly, 25 mg/kg per day and 50 mg/kg per day pravastatin and 5 mg/kg per day simvastatin promoted aneurysmal growth, and high-dose pravastatin induced aneurysmal rupture. The deleterious effects exerted by these statins were associated with an increase in apoptotic caspase-3 levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, suggesting that statins exert bidirectional effects.Conclusions-Our results provide the first evidence that cerebral aneurysm growth is partly associated with apoptosis and issue a warning that statins exert bidirectional effects on cerebral aneurysms. Additional intensive research is necessary to understand better their mechanisms and to identify patients in whom the administration of statins may elicit deleterious effects. (Stroke. 2011;42:2286-2293.)