Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release
Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release
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DOI：
10.1111/j.1471-4159.2006.04245.x
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发表时间：
2007-01-01
影响因子：
4.7
通讯作者：
Persidsky, Yuri
中科院分区：
文献类型：
--
作者：
Haorah, James;Knipe, Bryan;Persidsky, Yuri
脑微血管内皮细胞、周细胞和星形胶质细胞形成的血脑屏障控制着离子、多肽和白细胞的进出脑。由紧密连接蛋白(occludin、claudins和zonula occludens)组成的紧密连接(TJ)确保BMVEC单层的结构完整性。神经病理学研究表明，酗酒者血脑屏障受损；然而，血脑屏障功能障碍的潜在机制仍不清楚。利用原代人BMVEC，我们先前证明了乙醇(EtoH)代谢诱导的BMVEC氧化应激激活了肌球蛋白轻链激酶(MLCK)，导致细胞骨架或TJ蛋白的磷酸化增强，并导致BBB损伤。我们认为乙醇代谢产物可刺激1，4，5-三磷酸肌醇受体(IP3R)介导的细胞内钙(Ca~(2+))释放，从而激活BMVEC的MLCK。事实上，原代培养的人BMVEC用乙醇或其代谢产物处理后，IP3R蛋白的表达和IP3R门控的细胞内钙释放增加。这些功能变化与MLCK激活、细胞骨架/TJ蛋白磷酸化、BBB完整性丧失以及促进白细胞跨BMVEC单层迁移平行。抑制乙醇代谢或IP3R激活均可防止血脑屏障受损。这些发现表明，乙醇代谢产物通过刺激IP3R门控的BMVEC内钙释放，作为MLCK激活的信号分子。这些假定的事件可导致酒精中毒环境中的血脑屏障功能障碍，并导致促进白细胞跨血脑屏障迁移的神经炎性疾病。
The blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC), pericytes and astrocytes controls the transport of ions, peptides and leukocytes in and out of the brain. Tight junctions (TJ) composed of TJ proteins (occludin, claudins and zonula occludens) ensure the structural integrity of the BMVEC monolayer. Neuropathologic studies indicated that the BBB was impaired in alcohol abusers; however, the underlying mechanism of BBB dysfunction remains elusive. Using primary human BMVEC, we previously demonstrated that oxidative stress induced by ethanol (EtOH) metabolism in BMVEC activated myosin light chain kinase (MLCK), resulting in the enhanced phosphorylation of either cytoskeletal or TJ proteins, and in BBB impairment. We proposed that EtOH metabolites stimulated inositol 1,4,5-triphosphate receptor (IP3R)-operated intracellular calcium (Ca2+) release, thereby causing the activation of MLCK in BMVEC. Indeed, treatment of primary human BMVEC with EtOH or its metabolites resulted in the increased expression of IP3R protein and IP3R-gated intracellular Ca2+ release. These functional changes paralleled MLCK activation, phosphorylation of cytoskeletal/TJ proteins, loss of BBB integrity, and enhanced leukocyte migration across BMVEC monolayers. Inhibition of either EtOH metabolism or IP3R activation prevented BBB impairment. These findings suggest that EtOH metabolites act as signaling molecules for the activation of MLCK via the stimulation of IP3R-gated intracellular Ca2+ release in BMVEC. These putative events can lead to BBB dysfunction in the setting of alcoholism, and to neuro-inflammatory disorders promoting leukocyte migration across the BBB.