Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke

Abstract

Commissie Dierproeven). Experiments were approved by the responsible authority of the Regierung von Oberbayern (Germany) and the Institutional Ethics Committee of the Universidad Autónoma de Madrid. Author contributions AIC, PWMK, and EG performed in vivo and in vitro experiments and data analysis and contributed to writing the manuscript. TA performed immunological phenotyping, which DHB, VGD, and MHDA supervised. JE helped with data acquisition, and FL helped with sample collection. HHHWS designed experiments, contributed to writing the manuscript, and acquired funding. MGL, CK, and JE acquired funding and methods. JE helped with some in vitro experiments and animal breeding.

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy

“…18 Since Nox5 is absent from the rodent genome, mouse models expressing the human Nox5 gene have been developed. [40][41][42] In transgenic mice expressing Nox5 under the control of the Tie2 promoter, disruption of the blood-brain barrier due to stroke was increased in transgenic Nox5 mice, indicating a critical role for Nox5 in vascular integrity in the central nervous system. 40 Our findings in OIR are in agreement, with Nox5 overexpression in the vasculature, exacerbating breakdown of the BRB as reflected by increased vascular leakage and VEGF expression.…”

“…[40][41][42] In transgenic mice expressing Nox5 under the control of the Tie2 promoter, disruption of the blood-brain barrier due to stroke was increased in transgenic Nox5 mice, indicating a critical role for Nox5 in vascular integrity in the central nervous system. 40 Our findings in OIR are in agreement, with Nox5 overexpression in the vasculature, exacerbating breakdown of the BRB as reflected by increased vascular leakage and VEGF expression. Neovascularization within the inner retina and into the vitreous is a hallmark feature of end-stage proliferative DR, 2 however, this vascular pathology does not develop in diabetic rodents.…”

On the Clinical Pharmacology of Reactive Oxygen Species

“…Human NADPH oxidases are a family of seven transmembrane proteins, i.e., five mono-oxidases [NOX1, NOX2, NOX3, NOX4, and NOX5 (Wingler et al, 2011)] and two dual oxidases [DUOX1 and DUOX2 (van der Vliet et al, 2018)], each with specific tissue distribution and physiologic functions. Of these, NOX5 is the only one that is missing from the mouse and rat genome and requires knockin mouse models to be investigated in animal models, which has resulted in the fact that this isoform is preclinically understudied (Jha et al, 2017;Casas et al, 2019b;Touyz et al, 2019a,b). NOX1-4 catalytic units, but not NOX5, form a complex with the transmembrane protein p22phox and, further, with different cytosolic regulatory (e.g., p67phox or NOXA1; the small G protein Rac) and/or organizational protein partners (e.g., p47phox or NOXO1).…”

“…NOX4-derived H 2 O 2 leads to the pathologic fibrosis of liver (Lan et al, 2015) and lung (Carnesecchi et al, 2011) and bloodbrain barrier breakdown and neurodegeneration upon ischemic stroke (Kleinschnitz et al, 2010;Casas et al, 2017Casas et al, , 2019a, but it is surprisingly protective in atherosclerosis (Gray et al, 2016). NOX5 might be a suitable target in cardiovascular pathologies (Touyz et al, 2019a) and stroke (Casas et al, 2019b). DUOX2 and DUOXA2 loss-of-function mutations lead to congenital hypothyroidism (Weber et al, 2013) and can be targeted for radiation-induced thyroid cancer (Ameziane-El-Hassani et al, 2016).…”

NOX5 as a therapeutic target in cerebral ischemic injury

“…In this issue of the JCI, Casas et al provide new evidence that NOX5 promotes breakdown of the blood-brain barrier (BBB), increasing infarct size and worsening functional outcome after cerebral ischemia and reperfusion injury (3). This team made a knockin mouse harboring human NOX5 driven by the Tie2 promoter, which predominantly governs endothelial cell expression.…”