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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

Sites for direct NADPH oxidase inhibition. Some mechanisms of action have been reported for NADPHoxidase inhibitors. (1) Specific inhibition of the catalytic subunit (NOX). (2) Inhibition of theexpression of any subunit or inhibition of the traffic for subcellular location. (3) Flavin(cofactor) inhibition or electron transfer inhibition. (4) Inhibition of correct subunits assembly.(5) Inhibition of subunit phosphorylation (P) and activation.Abbreviations: FAD, flavin adenine dinucleotide; NADPH, reduced nicotinamide adeninedinucleotide phosphate; N-ter, amino terminal; O2−, superoxide anion.
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f5-vhrm-9-401: Sites for direct NADPH oxidase inhibition. Some mechanisms of action have been reported for NADPHoxidase inhibitors. (1) Specific inhibition of the catalytic subunit (NOX). (2) Inhibition of theexpression of any subunit or inhibition of the traffic for subcellular location. (3) Flavin(cofactor) inhibition or electron transfer inhibition. (4) Inhibition of correct subunits assembly.(5) Inhibition of subunit phosphorylation (P) and activation.Abbreviations: FAD, flavin adenine dinucleotide; NADPH, reduced nicotinamide adeninedinucleotide phosphate; N-ter, amino terminal; O2−, superoxide anion.

Mentions: Several compounds have the ability to inhibit NADPH oxidases directly (Table 1). In many cases, their effects have been confirmed in vivo, butmajor problems with the inhibitors currently available include low specificity, associated toxicity,or their peptide character. The search for successful inhibitors continues as the prospect for usein clinical practice increases along with molecular knowledge about redox signaling (Figure 5). Specific inhibitors are also essential toestablish fully the role of NADPH oxidases and individual NOX isoforms in different pathologies.


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)

Sites for direct NADPH oxidase inhibition. Some mechanisms of action have been reported for NADPHoxidase inhibitors. (1) Specific inhibition of the catalytic subunit (NOX). (2) Inhibition of theexpression of any subunit or inhibition of the traffic for subcellular location. (3) Flavin(cofactor) inhibition or electron transfer inhibition. (4) Inhibition of correct subunits assembly.(5) Inhibition of subunit phosphorylation (P) and activation.Abbreviations: FAD, flavin adenine dinucleotide; NADPH, reduced nicotinamide adeninedinucleotide phosphate; N-ter, amino terminal; O2−, superoxide anion.
© Copyright Policy
Related In: Results  -  Collection

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

f5-vhrm-9-401: Sites for direct NADPH oxidase inhibition. Some mechanisms of action have been reported for NADPHoxidase inhibitors. (1) Specific inhibition of the catalytic subunit (NOX). (2) Inhibition of theexpression of any subunit or inhibition of the traffic for subcellular location. (3) Flavin(cofactor) inhibition or electron transfer inhibition. (4) Inhibition of correct subunits assembly.(5) Inhibition of subunit phosphorylation (P) and activation.Abbreviations: FAD, flavin adenine dinucleotide; NADPH, reduced nicotinamide adeninedinucleotide phosphate; N-ter, amino terminal; O2−, superoxide anion.
Mentions: Several compounds have the ability to inhibit NADPH oxidases directly (Table 1). In many cases, their effects have been confirmed in vivo, butmajor problems with the inhibitors currently available include low specificity, associated toxicity,or their peptide character. The search for successful inhibitors continues as the prospect for usein clinical practice increases along with molecular knowledge about redox signaling (Figure 5). Specific inhibitors are also essential toestablish fully the role of NADPH oxidases and individual NOX isoforms in different pathologies.

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