TY - JOUR
T1 - Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke
AU - Casas, Ana I.
AU - Kleikers, Pamela W. M.
AU - Geuss, Eva
AU - Langhauser, Friederike
AU - Adler, Thure
AU - Busch, Dirk H.
AU - Gailus-Durner, Valerie
AU - de Angelis, Martin Hrabe
AU - Egea, Javier
AU - Lopez, Manuela G.
AU - Kleinschnitz, Christoph
AU - Schmidt, Harald H. H. W.
N1 - Funding Information:
This work was supported by the European Research Council, AdG RadMed 294683, an ERC PoC grant, SAVEBRAIN 139-101052, and H2020 project REPO-TRIAL (to HHHWS), the Spanish Ministry of Economy and Competence (SAF2015-63935R to MGL), the Deutsche Forschungsgemeinschaft (to CK), the Fondo de Investigaciones Sanitarias (CP14/00008 and PI16/00735 to JE), European Cooperation in Science and Technology and Koots-tra fellowships (to AIC), and the Bundesministerium für Bildung und Forschung Infrafrontier (01KX1012 to MHDA). A. Brouns-Strzelecka, J. Debets, and H. van Essen are gratefully acknowledged for their expert technical support. We thank K. Wingler for help with generating and breeding of NOX5KI mice.
Publisher Copyright:
© 2019 American Society for Clinical Investigation.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calciumactivated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, infarct volume, and functional outcomes were worsened in NOX5-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenationinduced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage.
AB - Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calciumactivated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, infarct volume, and functional outcomes were worsened in NOX5-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenationinduced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage.
KW - ANGIOGENESIS
KW - COUNT
KW - INDEPENDENT PREDICTOR
KW - INJURY
KW - NADPH OXIDASE
KW - NEUROPROTECTION
KW - THERAPEUTIC TARGETS
KW - Neuroprotection
KW - Injury
KW - Count
KW - Nadph oxidase
KW - Therapeutic targets
KW - Angiogenesis
KW - Independent predictor
U2 - 10.1172/jci124283
DO - 10.1172/jci124283
M3 - Article
C2 - 30882367
SN - 0021-9738
VL - 129
SP - 1772
EP - 1778
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -