Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats
Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats
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DOI：
10.1161/strokeaha.107.503086
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发表时间：
2008-04-01
期刊：
影响因子：
8.3
通讯作者：
Hashimoto, Nobuo
中科院分区：
文献类型：
--
作者：
Aoki, Tomohiro;Kataoka, Hiroharu;Hashimoto, Nobuo
背景和目的-脑动脉瘤（CA）的病理生理学与慢性炎症和血管壁细胞外基质降解有关。由于他汀类药物对各种血管疾病的保护作用独立于其降脂作用，我们研究了辛伐他汀对CA progression.Methods的影响-CA诱导在Sprague-道利大鼠与或不与口服辛伐他汀。动脉瘤诱导后3个月评价CA的大小和中膜厚度。通过逆转录-聚合酶链反应和免疫组化检测巨噬细胞趋化蛋白-1、血管细胞粘附分子-1、内皮型一氧化氮合酶、白细胞介素-1 β、诱导型一氧化氮合酶、基质金属蛋白酶-2和基质金属蛋白酶-9在平滑肌细胞壁中的表达。要检查辛伐他汀是否有抑制作用，对预先存在的CA，辛伐他汀管理开始在1个月后动脉瘤induction.Results -辛伐他汀治疗的大鼠表现出显着增加中膜厚度和显着减少与对照组大鼠相比，动脉瘤的大小。辛伐他汀治疗导致巨噬细胞趋化蛋白-1和血管细胞粘附分子-1的表达减少，内皮型一氧化氮合酶的表达增加，并减少巨噬细胞浸润的数量。在定量聚合酶链反应和免疫组化中，辛伐他汀显著抑制与CA进展相关的白细胞介素-1 β、诱导型一氧化氮合酶、基质金属蛋白酶-2和基质金属蛋白酶-9的表达上调。明胶酶谱显示辛伐他汀治疗后基质金属蛋白酶-2和基质金属蛋白酶-9活性降低。辛伐他汀也有效地抑制动脉瘤扩大和变薄的媒体预先存在的CAs.Conclusions -辛伐他汀治疗抑制CA的发展，通过抑制炎症反应在动脉瘤壁。辛伐他汀对既存CA的进展也有预防作用。辛伐他汀是预防CA进展的一种很有前途的新药物。
Background and Purpose - The pathophysiology of cerebral aneurysms ( CAs) is linked to chronic inflammation and degradation of extracellular matrix in vascular walls. Because statins have protective effects on various vascular diseases independent of their lipid- lowering effects, we investigated the effect of simvastatin on CA progression.Methods - CAs were induced in Sprague- Dawley rats with or without oral administration of simvastatin. The size and media thickness of CAs was evaluated 3 months after aneurysm induction. Expression of macrophage chemoattractant protein- 1, vascular cell adhesion molecule- 1, endothelial nitric oxide synthase, interleukin- 1 beta, inducible nitric oxide synthase, matrix metalloproteinase- 2, and matrix metalloproteinase- 9 in aneurysmal walls was examined by reverse transcriptase - polymerase chain reaction and immunohistochemistry. To examine whether simvastatin has a suppressive effect on preexisting CAs, simvastatin administration started at 1 month after aneurysm induction.Results - Rats treated with simvastatin exhibited a significant increase in media thickness and a significant reduction in aneurysmal size compared with control rats. Treatment with simvastatin resulted in reduced expression of macrophage chemoattractant protein- 1 and vascular cell adhesion molecule- 1, increased expression of endothelial nitric oxide synthase, and reduced the number of macrophage infiltration. In quantitative polymerase chain reaction and immunohistochemistry, simvastatin significantly inhibited upregulated expression of interleukin- 1 beta, inducible nitric oxide synthase, matrix metalloproteinase- 2, and matrix metalloproteinase- 9 associated with CA progression. Gelatin zymography revealed decreased activity of matrix metalloproteinase- 2 and matrix metalloproteinase- 9 in aneurysmal walls by simvastatin treatment. Simvastatin also effectively inhibited aneurysm enlargement and thinning of the media of preexisting CAs.Conclusions - Treatment with simvastatin suppresses the development of CAs by inhibiting inflammatory reactions in aneurysmal walls. Simvastatin also has a preventive effect on the progression of preexisting CAs. Simvastatin is a promising candidate of a novel medical treatment for the prevention of CA progression.