on October 4, 2007
Published online before print October 4, 2007, doi: 10.1161/STROKEAHA.107.489765
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Submitted on April 2, 2007
From the Institut für Kardiovaskuläre Physiologie (T.K., P.L., R.B., R.P.B.), and Klinik für Neurologie (T.K., H.S., T.N.-H.), Klinikum und Fachbereich Medizin der J.W. Goethe Universität, Frankfurt am Main; Klinik und Poliklinik für Neurologie (M.E.), Charite Campus Mitte, Berlin; and Institut für Biochemie (H.-J.G.), Westfälische Wilhelms Universität Münster, Münster, Germany. * To whom correspondence should be addressed. E-mail: r.brandes{at}em.uni-frankfurt.de.
Background and Purpose—Cerebral ischemia/reperfusion is associated with reactive oxygen species (ROS) generation, and NADPH oxidases are important sources of ROS. We hypothesized that NADPH oxidases mediate blood-brain barrier (BBB) disruption and contribute to tissue damage in ischemia/reperfusion. Methods—Ischemia was induced by filament occlusion of the middle cerebral artery in mice for 2 hours followed by reperfusion. BBB permeability was measured by Evans blue extravasation. Monolayer permeability was determined from transendothelial electrical resistance of cultured porcine brain capillary endothelial cells. Results—BBB permeability was increased in the ischemic hemisphere 1 hour after reperfusion. In NADPH oxidase–knockout (gp91phox-/-) mice, middle cerebral artery occlusion–induced BBB disruption and lesion volume were largely attenuated compared with those in wild-type mice. Inhibition of NADPH oxidase by apocynin prevented BBB damage. In porcine brain capillary endothelial cells, hypoxia/reoxygenation induced translocation of the NADPH oxidase activator Rac-1 to the membrane. In vivo inhibition of Rac-1 by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin or Clostridium difficile lethal toxin B also prevented the ischemia/reperfusion–induced BBB disruption. Stimulation of porcine brain capillary endothelial cells with H2O2 increased permeability, an effect attenuated by inhibition of phosphatidyl inositol 3-kinase or c-Jun N-terminal kinase but not blockade of extracellular signal–regulated kinase-1/2 or p38 mitogen-activated protein kinase. Inhibition of Rho kinase completely prevented the ROS-induced increase in permeability and the ROS-induced polymerization of the actin cytoskeleton. Conclusions—Activation of Rac and subsequently of the gp91phox containing NADPH oxidase promotes cerebral ROS formation, which then leads to Rho kinase–mediated endothelial cell contraction and disruption of the BBB. Inhibition of NAPDH oxidase is a promising approach to reduce brain injury after stroke.
Accepted on April 24, 2007
NADPH Oxidase Plays a Central Role in Blood-Brain Barrier Damage in Experimental Stroke
Timo Kahles MD;
Key words: endothelium • ischemia/reperfusion • oxidative stress • RhoA • statins
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