期刊
TRANSLATIONAL STROKE RESEARCH
卷 5, 期 5, 页码 618-626出版社
SPRINGER
DOI: 10.1007/s12975-014-0354-x
关键词
Ischemia-reperfusion; Brain microvascular endothelial cell; Autophagy; Blood-brain barrier
资金
- National Natural Science Foundation of China [81171105, 81271300, 81371279]
- Jiangsu Province's Outstanding Medical Academic Leader program [LJ201139]
- National Key Technology R&D program for the 12th Five-year plan of the People's Republic of China [2011BAI08B05, 2011BAI08B06, 2014BAZ04810]
- Scientific Department of Jiangsu Province [BL2014045]
- Suzhou Government [LCZX201301, SZS201413, SYS201332]
Brain microvascular endothelial cell (BMVEC) injury induced by ischemia-reperfusion (I/R) is the initial phase of blood-brain barrier (BBB) disruption, which results in a poor prognosis for ischemic stroke patients. Autophagy occurs in ischemic brain and has been shown to exhibit protective effects on endothelial cell against stress. However, the potential effects of BMVEC autophagy on BBB permeability during I/R and the mechanisms underlying these effects have yet to be elucidated. In the current study, we answered these questions by using chemical modulators of autophagy, including rapamycin and lithium carbonate acting, respectively, as mammalian target of rapamycin (mTOR)-dependent and mTOR-independent autophagy inducers and 3-methyladenine (3-MA) as an autophagy inhibitor. To mimic I/R injury, BMVECs were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), and a rat transient middle cerebral artery occlusion/reperfusion (MCAO/R) model was performed. All the drugs were given at 0.5 h before OGD/R or MCAO/R. First, enhancement of autophagy by rapamycin and lithium carbonate attenuated, whereas suppression of autophagy by 3-MA intensified BMVEC apoptosis and the high level of ROS induced by OGD/R. In addition, rapamycin and lithium carbonate pretreatments significantly reversed the decreased level of tight junction protein zonula occludens-1 (ZO-1) induced by OGD/R and promoted the distribution of ZO-1 on cell membranes. Finally, pretreatments with rapamycin and lithium carbonate reduced evans blue extravasation and brain water content in the ischemic hemisphere of the rat. In contrast, 3-MA pretreatment exerted opposite effects both in vitro and in vivo. These results may indicate a beneficial effect of BMVEC autophagy on BBB integrity during I/R injury.
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