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Current status of NADPH oxidase research in cardiovascular pharmacology.

Rodiño-Janeiro BK, Paradela-Dobarro B, Castiñeiras-Landeira MI, Raposeiras-Roubín S, González-Juanatey JR, Alvarez E - Vasc Health Risk Manag (2013)

Bottom Line: From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability.However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds.High-throughput screens for any of these activities could provide new inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain.

ABSTRACT
The implications of reactive oxygen species in cardiovascular disease have been known for some decades. Rationally, therapeutic antioxidant strategies combating oxidative stress have been developed, but the results of clinical trials have not been as good as expected. Therefore, to move forward in the design of new therapeutic strategies for cardiovascular disease based on prevention of production of reactive oxygen species, steps must be taken on two fronts, ie, comprehension of reduction-oxidation signaling pathways and the pathophysiologic roles of reactive oxygen species, and development of new, less toxic, and more selective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors, to clarify both the role of each NADPH oxidase isoform and their utility in clinical practice. In this review, we analyze the value of NADPH oxidase as a therapeutic target for cardiovascular disease and the old and new pharmacologic agents or strategies to prevent NADPH oxidase activity. Some inhibitors and different direct or indirect approaches are available. Regarding direct NADPH oxidase inhibition, the specificity of NADPH oxidase is the focus of current investigations, whereas the chemical structure-activity relationship studies of known inhibitors have provided pharmacophore models with which to search for new molecules. From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability. However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds. Likewise, some different approaches include inhibition of assembly of the NADPH oxidase complex, subcellular translocation, post-transductional modifications, calcium entry/release, electron transfer, and genetic expression. High-throughput screens for any of these activities could provide new inhibitors. All this knowledge and the research presently underway will likely result in development of new drugs for inhibition of NADPH oxidase and application of therapeutic approaches based on their action, for the treatment of cardiovascular disease in the next few years.

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Related in: MedlinePlus

Possible strategies for NADPH oxidase inhibition. Several steps that can be used to modulateNADPH oxidase activity. (1) NADPH oxidase subunits expression. (2) Signaling upstream of NADPHoxidase activation. (3) Association of cytosolic subunits and formation of the complete enzymecomplex. (4) Subunit phosphorylation (P) and activation. (5) Modulation of cytosolic calciumconcentration. (6) Transference of electrons through the enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; e−,electron; FAD, flavin adenine dinucleotide; HSP90, heat shock protein 90; NADPH, nicotinamideadenine dinucleotide phosphate; O2−, superoxide anion; O2, oxygen.
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f4-vhrm-9-401: Possible strategies for NADPH oxidase inhibition. Several steps that can be used to modulateNADPH oxidase activity. (1) NADPH oxidase subunits expression. (2) Signaling upstream of NADPHoxidase activation. (3) Association of cytosolic subunits and formation of the complete enzymecomplex. (4) Subunit phosphorylation (P) and activation. (5) Modulation of cytosolic calciumconcentration. (6) Transference of electrons through the enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; e−,electron; FAD, flavin adenine dinucleotide; HSP90, heat shock protein 90; NADPH, nicotinamideadenine dinucleotide phosphate; O2−, superoxide anion; O2, oxygen.

Mentions: Due to the complex relationship between NADPH oxidases and other proteins in the context of somesignaling pathways and even the complex cross-talk between different signaling pathways, inhibitionof NADPH oxidase activity can be done sometimes via regulation of a pathway rather than directinhibition of the oxidase. This possibility has been considered in clinical practice because it hasnot been easy to obtain specific and selective inhibitors for each NADPH oxidase isoform. Therefore,at the moment, direct and indirect inhibition of NADPH oxidase activity should be considered asstrategies with the same objective (Figure 4).


Current status of NADPH oxidase research in cardiovascular pharmacology.

Rodiño-Janeiro BK, Paradela-Dobarro B, Castiñeiras-Landeira MI, Raposeiras-Roubín S, González-Juanatey JR, Alvarez E - Vasc Health Risk Manag (2013)

Possible strategies for NADPH oxidase inhibition. Several steps that can be used to modulateNADPH oxidase activity. (1) NADPH oxidase subunits expression. (2) Signaling upstream of NADPHoxidase activation. (3) Association of cytosolic subunits and formation of the complete enzymecomplex. (4) Subunit phosphorylation (P) and activation. (5) Modulation of cytosolic calciumconcentration. (6) Transference of electrons through the enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; e−,electron; FAD, flavin adenine dinucleotide; HSP90, heat shock protein 90; NADPH, nicotinamideadenine dinucleotide phosphate; O2−, superoxide anion; O2, oxygen.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750863&req=5

f4-vhrm-9-401: Possible strategies for NADPH oxidase inhibition. Several steps that can be used to modulateNADPH oxidase activity. (1) NADPH oxidase subunits expression. (2) Signaling upstream of NADPHoxidase activation. (3) Association of cytosolic subunits and formation of the complete enzymecomplex. (4) Subunit phosphorylation (P) and activation. (5) Modulation of cytosolic calciumconcentration. (6) Transference of electrons through the enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; e−,electron; FAD, flavin adenine dinucleotide; HSP90, heat shock protein 90; NADPH, nicotinamideadenine dinucleotide phosphate; O2−, superoxide anion; O2, oxygen.
Mentions: Due to the complex relationship between NADPH oxidases and other proteins in the context of somesignaling pathways and even the complex cross-talk between different signaling pathways, inhibitionof NADPH oxidase activity can be done sometimes via regulation of a pathway rather than directinhibition of the oxidase. This possibility has been considered in clinical practice because it hasnot been easy to obtain specific and selective inhibitors for each NADPH oxidase isoform. Therefore,at the moment, direct and indirect inhibition of NADPH oxidase activity should be considered asstrategies with the same objective (Figure 4).

Bottom Line: From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability.However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds.High-throughput screens for any of these activities could provide new inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain.

ABSTRACT
The implications of reactive oxygen species in cardiovascular disease have been known for some decades. Rationally, therapeutic antioxidant strategies combating oxidative stress have been developed, but the results of clinical trials have not been as good as expected. Therefore, to move forward in the design of new therapeutic strategies for cardiovascular disease based on prevention of production of reactive oxygen species, steps must be taken on two fronts, ie, comprehension of reduction-oxidation signaling pathways and the pathophysiologic roles of reactive oxygen species, and development of new, less toxic, and more selective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors, to clarify both the role of each NADPH oxidase isoform and their utility in clinical practice. In this review, we analyze the value of NADPH oxidase as a therapeutic target for cardiovascular disease and the old and new pharmacologic agents or strategies to prevent NADPH oxidase activity. Some inhibitors and different direct or indirect approaches are available. Regarding direct NADPH oxidase inhibition, the specificity of NADPH oxidase is the focus of current investigations, whereas the chemical structure-activity relationship studies of known inhibitors have provided pharmacophore models with which to search for new molecules. From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability. However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds. Likewise, some different approaches include inhibition of assembly of the NADPH oxidase complex, subcellular translocation, post-transductional modifications, calcium entry/release, electron transfer, and genetic expression. High-throughput screens for any of these activities could provide new inhibitors. All this knowledge and the research presently underway will likely result in development of new drugs for inhibition of NADPH oxidase and application of therapeutic approaches based on their action, for the treatment of cardiovascular disease in the next few years.

Show MeSH
Related in: MedlinePlus