期刊
EXPERIMENTAL AND MOLECULAR PATHOLOGY
卷 97, 期 3, 页码 386-392出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yexmp.2014.09.006
关键词
AMPK; LPS; BBB; NAD(P)H oxidase; ROS; Aging
类别
资金
- National Basic Research Program of China [2013CB530700]
- National Natural Science Foundation of China [81370411]
- Provincial Natural Science Foundation of Hunan [11JJ5068]
- Healthy Department of Hunan Province [B2011-078]
- Department of Science and Technology of Hunan Province [2013FJ3119]
The blood-brain barrier (BBB), formed by specialized brain endothelial cells that are interconnected by tight junctions, strictly regulates paracellular permeability to maintain an optimal extracellular environment for brain homeostasis. Lipopolysaccharide (LPS) is known to alter the integrity of the BBB in sepsis, although the underlying mechanism remains unknown. The aim of this study was to elucidate the molecular mechanisms underlying the disruption of the BBB in LPS-induced sepsis and to determine whether the activation of AMP-activated protein kinase (AMPK) prevents LPS-induced BBB dysfunction. The exposure of human brain microvascular endothelial cells (HBMECs) to LPS (1 mu g/ml) for 4 to 24 ha week dramatically increased the permeability of the BBB in parallel with the lowered expression levels of occludin and claudin-5, which are essential to maintain tight junctions in HBMECs. In addition, LPS significantly increased the reactive oxygen species (ROS) productions. All effects induced by LPS in HBVMCs were reversed by adenoviral overexpression of superoxide dismutase, inhibition of NAD(P)H oxidase by apocynin or gain-function of AMPK by adenoviral overexpression of constitutively active mutant (AMPK-CA) or by 5-amino-4-imidazole carboxamide riboside (AICAR). Finally, the upregulation of AMPK by either AMPK-CA or AICAR abolished the levels of LPS-enhanced NAD(P)H oxidase subunit protein expressions. We conclude that AMPK activation improves the integrity of the BBB disrupted by LPS through suppressing the induction of NAD(P)H oxidase-derived ROS in HBMECs. (C) 2014 Elsevier Inc. All rights reserved.
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