title: SFRR-E Young Investigator AwardeeNOXing out stroke: Identification of NOX4 and 5as targets in blood-brain-barrier stabilisation and neuroprotection.
abstract: Stroke is the second leading cause of death with high blood pressure and female gender being the main risk factors. However, only one treatment is available and with many contraindications, which leaves more than 80% of patients untreated. Over a thousand experimental stroke treatments have remained unsuccessful in the clinic. In preclinical research, low reproducibility and publication bias have been suggested as causes of low translatability success. NADPH oxidases might be key players in stroke via their unique role as a major and/or early source of reactive oxygen species (ROS). To clarify the role of the different NOX isoforms (1, 2, 4, and 5) we analysed different KO and KI models. Previous literature claimed a role for NOX2. Using both a meta-analytical and a blinded randomised controlled trial approach, we however find that NOX2 plays only a minor role and publication bias and lack of power perturbed the published literature. We earlier showed a detrimental role of NOX4 in stroke and extend this based on cell-specific KO animals that endothelial but not vascular smooth muscle cells are the major source of NOX4 in stroke. Mice do not express the human NOX5 gene. Using a NOX5 KI model, we show that endothelial NOX5 induces hypertension and increased stroke risk, particularly in females. In human hypertension, NOX5 is upregulated, and women have a higher stroke risk. Thus NOX5 might be a missing link in this context. In conclusion, NOX4 and NOX5, but not NOX2, are promising targets for the development of new neuroprotective therapies for ischemic stroke. A priori power and sample size calculation as well as reporting of also negative data is essential with respect to preclinical validation of therapeutic targets.
authors.affiliation: Maastricht University (Faculty of Health, Medicine and Life Sciences), Department of pharmacology, The Netherlands. Electronic address: p.kleikers@maastrichtuniversity.nl.
authors.forename: P W M
authors.initials: PW
authors.lastname: Kleikers
authors.affiliation: Maastricht University (Faculty of Health, Medicine and Life Sciences), Department of pharmacology, The Netherlands.
authors.forename: V T
authors.initials: VT
authors.lastname: Dao
authors.affiliation: Universität Würzburg, Neurologische Klinik und Poliklinik, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Göb
authors.affiliation: Radboud Universiteit Nijmegen, SYRCLE and Central Animal Laboratory, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Hooijmans
authors.affiliation: Maastricht University (Faculty of Health, Medicine and Life Sciences), Department of pharmacology, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Debets
authors.affiliation: Maastricht University (Faculty of Health, Medicine and Life Sciences), Department of pharmacology, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Essen
authors.affiliation: Universität Würzburg, Neurologische Klinik und Poliklinik, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Maastricht University (Faculty of Health, Medicine and Life Sciences), Department of pharmacology, The Netherlands.
authors.forename: H H H W
authors.initials: HH
authors.lastname: Schmidt