Deficiency of brain ATP-binding cassette transporter A-1 exacerbates blood-brain barrier and white matter damage after stroke.
Deficiency of brain ATP-binding cassette transporter A-1 exacerbates blood-brain barrier and white matter damage after stroke.
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DOI：
10.1161/strokeaha.114.007145
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发表时间：
2015-03
期刊：
影响因子：
8.3
通讯作者：
Chen J
中科院分区：
文献类型：
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作者：
Cui X;Chopp M;Zacharek A;Karasinska JM;Cui Y;Ning R;Zhang Y;Wang Y;Chen J
atp结合盒转运蛋白a -1 （ABCA1）基因是转录因子肝x受体（LXRs）的关键靶点。LXR活化对动物缺血性脑卒中模型具有抗炎和神经保护作用。在这里，我们验证了脑ABCA1减少脑缺血后血脑屏障（BBB）和白质（WM）损伤的假设。成年脑特异性ABCA1缺陷（ABCA1−B/−B）和floxcontrol （ABCA1fl/fl）小鼠进行永久性大脑中远端动脉闭塞（dMCAo），并在dMCAo后7天处死。分析功能结果、梗死体积、血脑屏障渗漏和脑损伤。与ABCA1fl/fl小鼠相比，ABCA1−B/−B小鼠病变体积略有增加（P=0.052），但缺血性脑血脑屏障渗漏和脑损伤明显增加，神经功能缺损更为严重。脑abca1缺陷小鼠缺血脑组织基质金属蛋白酶-9 （MMP9）水平升高，胰岛素样生长因子-1 （IGF1）水平降低。血脑屏障渗漏与水通道蛋白-4 （AQP4）表达呈负相关（r= - 0.073， P<0.05）。在ABCA1−B/−B小鼠的星形胶质细胞培养物中，IGF1和AQP4的表达减少，而MMP9的表达上调。与ABCA1 - B/ - B星形胶质细胞条件培养基培养的C57BL/6野生型小鼠相比，ABCA1 - B/ - B星形胶质细胞条件培养基培养的原代皮质神经元（pcn）的神经突生长减少。ABCA1−B/−B pcn显示神经突生长明显减少，IGF1处理可减弱神经突生长。我们证明脑abca1缺乏会增加脑血脑屏障渗漏、WM/轴突损伤和脑卒中后的功能缺陷。同时IGF1的降低和MMP9的上调可能导致脑abca1缺乏症引起脑缺血血脑屏障和WM/轴突损伤。
The ATP-binding cassette transporter A-1 (ABCA1) gene is a key target of the transcription factors liver-X-receptors (LXRs). LXR activation has anti-inflammatory and neuroprotective effects in animal ischemic stroke models. Here, we tested the hypothesis that brain ABCA1 reduces blood-brain barrier (BBB) and white matter (WM) impairment in the ischemic brain after stroke. Adult brain-specific ABCA1 deficient (ABCA1−B/−B) and floxed-control (ABCA1fl/fl) mice were subjected to permanent distal middle cerebral artery occlusion (dMCAo) and were sacrificed 7 days after dMCAo. Functional outcome, infarct volume, BBB leakage, and WM-damage were analyzed. Compared to ABCA1fl/fl mice, ABCA1−B/−B mice showed marginally (P=0.052) increased lesion volume, but significantly increased BBB leakage and WM-damage in the ischemic brain, and more severe neurological deficits. Brain-ABCA1 deficient mice exhibited increased the level of matrix-metalloproteinase-9 (MMP9) and reduced the level of insulin-like growth factor-1 (IGF1) in the ischemic brain. BBB leakage was inversely correlated (r=−0.073, P<0.05) with aquaporin-4 (AQP4) expression. Reduction of IGF1 and AQP4, but upregulation of MMP9 expression were also found in the primary astrocyte-cultures derived from ABCA1−B/−B mice. Cultured primary-cortical-neurons (PCNs) derived from C57BL/6 wild-type mice with ABCA1−B/−B astrocyte-conditioned-medium exhibited decreased neurite-outgrowth compared to culture with ABCA1fl/fl astrocyte-conditioned-medium. ABCA1−B/−B PCNs show significantly decreased neurite-outgrowth, which was attenuated by IGF1 treatment. We demonstrate that brain ABCA1-deficiency increases BBB leakage, WM/axonal damage and functional deficits after stroke. Concomitant reduction of IGF1 and upregulation of MMP9 may contribute to brain ABCA1-deficiency induced BBB and WM/axonal damage in the ischemic brain.