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The 1027th target candidate in stroke: Will NADPH oxidase hold up?

Radermacher KA, Wingler K, Kleikers P, Altenhöfer S, Jr Hermans J, Kleinschnitz C, Hhw Schmidt H - Exp Transl Stroke Med (2012)

Bottom Line: Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources.Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS.Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. h.schmidt@maastrichtuniversity.nl.

ABSTRACT
As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.

No MeSH data available.


Related in: MedlinePlus

Relevant NOX isoforms in stroke and their respective subunit requirements (adapted from[46]). NOX2, as well as NOX4, seem to be implicated in stoke. Known regulatory proteins are associated with individual isoforms. Activator proteins are coloured in green and organizing proteins in blue. Both isoforms form functional dimers with p22phox. p47phox phosphorylation subsequently causes the cytosolic subunits p47phox, p67phox, and p40phox to translocate into membranes and fuse with the catalytic subunit NOX2. This is followed by interaction between Rac and NOX2. Nox4 forms a dimer with p22phox. Although NOX4 does not appear to require additional regulators, recently some NOX4 binding proteins (DPI and PolDip2) have been discovered whose role needs to be further elucidated. Potential target sites of NADPH oxidase inhibitors are also shown in the scheme.
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Figure 1: Relevant NOX isoforms in stroke and their respective subunit requirements (adapted from[46]). NOX2, as well as NOX4, seem to be implicated in stoke. Known regulatory proteins are associated with individual isoforms. Activator proteins are coloured in green and organizing proteins in blue. Both isoforms form functional dimers with p22phox. p47phox phosphorylation subsequently causes the cytosolic subunits p47phox, p67phox, and p40phox to translocate into membranes and fuse with the catalytic subunit NOX2. This is followed by interaction between Rac and NOX2. Nox4 forms a dimer with p22phox. Although NOX4 does not appear to require additional regulators, recently some NOX4 binding proteins (DPI and PolDip2) have been discovered whose role needs to be further elucidated. Potential target sites of NADPH oxidase inhibitors are also shown in the scheme.

Mentions: NOX2 was the first isoform identified and thus is the best-studied isoform. Subunits that are needed for NOX2 activation are divided into two groups: activating molecules (p67phox) and organizing molecules (p47phox). Upon phosphorylation of p47phox, cytosolic subunits (p40phox, p47phox and p67phox) translocate to the cell membrane and bind to intracellular loops of NOX2. Activators bind to Rac in the cytosol and then migrate towards NOX2 with help of the organizers [41] (Figure 1). For ROS production by NOX2, Rac and p47phox have to be activated simultaneously.


The 1027th target candidate in stroke: Will NADPH oxidase hold up?

Radermacher KA, Wingler K, Kleikers P, Altenhöfer S, Jr Hermans J, Kleinschnitz C, Hhw Schmidt H - Exp Transl Stroke Med (2012)

Relevant NOX isoforms in stroke and their respective subunit requirements (adapted from[46]). NOX2, as well as NOX4, seem to be implicated in stoke. Known regulatory proteins are associated with individual isoforms. Activator proteins are coloured in green and organizing proteins in blue. Both isoforms form functional dimers with p22phox. p47phox phosphorylation subsequently causes the cytosolic subunits p47phox, p67phox, and p40phox to translocate into membranes and fuse with the catalytic subunit NOX2. This is followed by interaction between Rac and NOX2. Nox4 forms a dimer with p22phox. Although NOX4 does not appear to require additional regulators, recently some NOX4 binding proteins (DPI and PolDip2) have been discovered whose role needs to be further elucidated. Potential target sites of NADPH oxidase inhibitors are also shown in the scheme.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3403875&req=5

Figure 1: Relevant NOX isoforms in stroke and their respective subunit requirements (adapted from[46]). NOX2, as well as NOX4, seem to be implicated in stoke. Known regulatory proteins are associated with individual isoforms. Activator proteins are coloured in green and organizing proteins in blue. Both isoforms form functional dimers with p22phox. p47phox phosphorylation subsequently causes the cytosolic subunits p47phox, p67phox, and p40phox to translocate into membranes and fuse with the catalytic subunit NOX2. This is followed by interaction between Rac and NOX2. Nox4 forms a dimer with p22phox. Although NOX4 does not appear to require additional regulators, recently some NOX4 binding proteins (DPI and PolDip2) have been discovered whose role needs to be further elucidated. Potential target sites of NADPH oxidase inhibitors are also shown in the scheme.
Mentions: NOX2 was the first isoform identified and thus is the best-studied isoform. Subunits that are needed for NOX2 activation are divided into two groups: activating molecules (p67phox) and organizing molecules (p47phox). Upon phosphorylation of p47phox, cytosolic subunits (p40phox, p47phox and p67phox) translocate to the cell membrane and bind to intracellular loops of NOX2. Activators bind to Rac in the cytosol and then migrate towards NOX2 with help of the organizers [41] (Figure 1). For ROS production by NOX2, Rac and p47phox have to be activated simultaneously.

Bottom Line: Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources.Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS.Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. h.schmidt@maastrichtuniversity.nl.

ABSTRACT
As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.

No MeSH data available.


Related in: MedlinePlus