Cui Xu, Chopp Michael, Zhang Zhenggang, Li Rongwen, Zacharek Alex, Landschoot-Ward Julie, Venkat Poornima, Chen Jieli
From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
Stroke. 2017 Feb;48(2):459-467. doi: 10.1161/STROKEAHA.116.015592. Epub 2016 Dec 27.
ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke.
Middle-aged male specific brain ABCA1-deficient (ABCA1) and floxed-control (ABCA1) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1 stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo.
No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1 ischemic mice, ABCA1 ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1 ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1 ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-induced deficits. In vitro, GW3965 treatment (5 μM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1 embryos, but not in neurons derived from ABCA1 embryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1 embryos.
ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.
ATP结合盒转运蛋白A1（ABCA1）是主要的逆向胆固醇转运蛋白，在脑高密度脂蛋白（HDL）胆固醇的形成中起关键作用。载脂蛋白E（ApoE）是脑中含量最丰富的载脂蛋白，可将胆固醇转运至脑细胞中。ABCA1和ApoE受肝X受体上调。肝X受体的激活对中风具有神经修复益处。本研究探讨ABCA1/ApoE/HDL通路是否介导合成型双肝X受体激动剂GW3965诱导的中风后神经修复。
对中年雄性特异性脑ABCA1缺陷（ABCA1）小鼠和对照（ABCA1）小鼠进行大脑中动脉远端闭塞（dMCAo），并在dMCAo后24小时开始，每天给ABCA1中风小鼠灌胃生理盐水或GW3965（10 mg/kg），或脑室内注入人工脑脊液或人血浆HDL3，直至dMCAo后14天安乐死。
各组之间总胆固醇和甘油三酯的血液水平及梗死体积无差异。与ABCA1缺血小鼠相比，ABCA1缺血小鼠在dMCAo后14天功能结局受损，ABCA1/ApoE表达降低，缺血边界区灰质/白质密度降低。用GW3965治疗ABCA1缺血小鼠可导致脑ABCA1/ApoE表达增加，同时血液HDL、缺血边界区灰质/白质密度和少突胶质前体细胞数量增加，以及dMCAo后14天功能结局改善。GW3965治疗对ABCA1缺血小鼠的有益作用可忽略不计。然而，脑室内注入人血浆HDL3可显著减轻ABCA1诱导的缺陷。在体外，GW3965处理（5 μM）可增加源自ABCA1胚胎的原代皮质神经元中ABCA1/突触素水平及神经突/轴突生长，但对源自ABCA1胚胎的神经元无此作用。HDL处理（80 μg/mL）可减轻源自ABCA1胚胎的神经元中神经突/轴突生长的减少。
ABCA1/ApoE/HDL通路至少部分促成了GW3965诱导的中风后神经修复。
