Increased Blood-Brain Barrier Permeability and Brain Edema After Focal Cerebral Ischemia Induced by Hyperlipidemia Role of Lipid Peroxidation and Calpain-1/2, Matrix Metalloproteinase-2/9, and RhoA Overactivation
Increased Blood-Brain Barrier Permeability and Brain Edema After Focal Cerebral Ischemia Induced by Hyperlipidemia Role of Lipid Peroxidation and Calpain-1/2, Matrix Metalloproteinase-2/9, and RhoA Overactivation
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DOI：
10.1161/strokeaha.111.615559
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发表时间：
2011-11-01
期刊：
影响因子：
8.3
通讯作者：
Hermann, Dirk M.
中科院分区：
文献类型：
--
作者：
Elali, Ayman;Doeppner, Thorsten R.;Hermann, Dirk M.
背景和目的：高脂血症是缺血性脑卒中的高危因素。到目前为止，它对脑损伤和血脑屏障通透性的影响尚未在缺血性中风的动物模型中进行评估。方法：野生型和载脂蛋白E（-/-）小鼠分别饲喂正常或高胆固醇高脂肪食物，阻断大脑中动脉30分钟。再灌注24小时后观察缺血损伤、脑水肿、IgG外渗、脂质过氧化、calpain-1/2、基质金属蛋白酶-2/9、RhoA活化、occludin表达。结果：高胆固醇食物，而非载脂蛋白E缺乏，增加了IgG外渗和脑水肿，但不影响梗死面积和DNA碎片细胞密度。高脂血症小鼠脑内脂质过氧化和低密度脂蛋白氧化增加，并与calpain-1/2和基质金属蛋白酶-2/9激活增加、RhoA及其鸟嘌呤交换因子白血病相关鸟嘌呤交换因子过度激活、脑微血管紧密连接蛋白occludin下调有关。结论：在高脂血症期间，缺血后血脑屏障通透性和脑水肿增加，这表明了认识和适当治疗这种高度流行疾病的重要性。转化研究应该更充分地模拟人类中风中普遍存在的危险因素。（中风。2011;42:3238-3244）
Background and Purpose-Hyperlipidemia is a highly prevalent risk factor for ischemic stroke. Its impact on brain injury and blood-brain barrier permeability, so far, has not been assessed in animal models of ischemic stroke.Methods-Wild-type and apolipoprotein E(-/-) mice, fed with normal or cholesterol-rich high-fat food, were subjected to 30 minutes of middle cerebral artery occlusion. Ischemic injury, brain edema, IgG extravasation, lipid peroxidation, calpain-1/2, matrix metalloproteinase-2/9, and RhoA activation, and occludin expression were evaluated 24 hours after reperfusion.Results-Cholesterol-rich food, but not apolipoprotein E deficiency, increased IgG extravasation and brain edema without influencing infarct area and the density of DNA fragmented cells. Increased lipid peroxidation and low-density lipoprotein oxidation were noticed in the brain of hyperlipidemic mice and were associated with increased activation of calpain-1/2 and matrix metalloproteinase-2/9, overactivation of RhoA and its guanine exchange factor leukemia-associated guanine exchange factor, and downregulation of the tight junction protein occludin in cerebral microvessels.Conclusions-That postischemic blood-brain barrier permeability and brain edema are increased during hyperlipidemia points toward the importance of the recognition and adequate treatment of this highly prevalent condition. Translational studies should more adequately mimic risk factors prevalent in human stroke. (Stroke. 2011; 42:3238-3244.)