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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

Indirect inhibition of NADPH oxidase. Points for NADPH oxidase activity inhibition or reductionof the enzyme’s expression. The stimulating effects of the renin-angiotensin-aldosteronesystem (RAAS) on NADPH oxidase activity can be stopped by the inhibition of renin, angiotensinconverting enzyme (ACE) or blockage of angiotensin II receptor 1 (AT1) or aldosterone receptor.Protein kinase C inhibition reduces NADPH oxidase phosphorylation (P) and expression. Glucagon-likepeptide-1 and tyrosine kinase inhibition reduce the activity and the expression of NADPH oxidases.Sirtuins reduce NOX1 expression, whereas calcium channel blockers reduce NOX5 activity and statinsdecrease cytosolic subunit translocation to the membrane-fixed enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; FAD, flavin adeninedinucleotide; HSP90, heat shock protein 90; NADPH, reduced nicotinamide adenine dinucleotidephosphate; Tyr-K, tyrosine kinase.
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f6-vhrm-9-401: Indirect inhibition of NADPH oxidase. Points for NADPH oxidase activity inhibition or reductionof the enzyme’s expression. The stimulating effects of the renin-angiotensin-aldosteronesystem (RAAS) on NADPH oxidase activity can be stopped by the inhibition of renin, angiotensinconverting enzyme (ACE) or blockage of angiotensin II receptor 1 (AT1) or aldosterone receptor.Protein kinase C inhibition reduces NADPH oxidase phosphorylation (P) and expression. Glucagon-likepeptide-1 and tyrosine kinase inhibition reduce the activity and the expression of NADPH oxidases.Sirtuins reduce NOX1 expression, whereas calcium channel blockers reduce NOX5 activity and statinsdecrease cytosolic subunit translocation to the membrane-fixed enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; FAD, flavin adeninedinucleotide; HSP90, heat shock protein 90; NADPH, reduced nicotinamide adenine dinucleotidephosphate; Tyr-K, tyrosine kinase.

Mentions: In addition to direct inhibition of NADPH oxidase, some drugs have the ability to regulatesignaling pathways that participate in activation of NADPH oxidase activity. The main mechanismsinvolved in this effect are inhibition of the regulating NADPH oxidase subunits, by reduction oftheir phosphorylation or by blocking their translocation to the membrane complex of the enzyme, orreduction of the expression of one or more NADPH oxidase subunits (Figure 6). Interestingly, some drugs with this ability are commonly usedin cardiovascular disease. Therefore, it is reasonable to think that, in addition to the primarymechanisms of action of these drugs, regulation of NADPH oxidase activity at the vascular levelcould also contribute to their beneficial effects.


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)

Indirect inhibition of NADPH oxidase. Points for NADPH oxidase activity inhibition or reductionof the enzyme’s expression. The stimulating effects of the renin-angiotensin-aldosteronesystem (RAAS) on NADPH oxidase activity can be stopped by the inhibition of renin, angiotensinconverting enzyme (ACE) or blockage of angiotensin II receptor 1 (AT1) or aldosterone receptor.Protein kinase C inhibition reduces NADPH oxidase phosphorylation (P) and expression. Glucagon-likepeptide-1 and tyrosine kinase inhibition reduce the activity and the expression of NADPH oxidases.Sirtuins reduce NOX1 expression, whereas calcium channel blockers reduce NOX5 activity and statinsdecrease cytosolic subunit translocation to the membrane-fixed enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; FAD, flavin adeninedinucleotide; HSP90, heat shock protein 90; NADPH, reduced nicotinamide adenine dinucleotidephosphate; Tyr-K, tyrosine kinase.
© Copyright Policy
Related In: Results  -  Collection

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

f6-vhrm-9-401: Indirect inhibition of NADPH oxidase. Points for NADPH oxidase activity inhibition or reductionof the enzyme’s expression. The stimulating effects of the renin-angiotensin-aldosteronesystem (RAAS) on NADPH oxidase activity can be stopped by the inhibition of renin, angiotensinconverting enzyme (ACE) or blockage of angiotensin II receptor 1 (AT1) or aldosterone receptor.Protein kinase C inhibition reduces NADPH oxidase phosphorylation (P) and expression. Glucagon-likepeptide-1 and tyrosine kinase inhibition reduce the activity and the expression of NADPH oxidases.Sirtuins reduce NOX1 expression, whereas calcium channel blockers reduce NOX5 activity and statinsdecrease cytosolic subunit translocation to the membrane-fixed enzyme complex.Abbreviations: Ca2+, calcium ion; CaM, calmodulin; FAD, flavin adeninedinucleotide; HSP90, heat shock protein 90; NADPH, reduced nicotinamide adenine dinucleotidephosphate; Tyr-K, tyrosine kinase.
Mentions: In addition to direct inhibition of NADPH oxidase, some drugs have the ability to regulatesignaling pathways that participate in activation of NADPH oxidase activity. The main mechanismsinvolved in this effect are inhibition of the regulating NADPH oxidase subunits, by reduction oftheir phosphorylation or by blocking their translocation to the membrane complex of the enzyme, orreduction of the expression of one or more NADPH oxidase subunits (Figure 6). Interestingly, some drugs with this ability are commonly usedin cardiovascular disease. Therefore, it is reasonable to think that, in addition to the primarymechanisms of action of these drugs, regulation of NADPH oxidase activity at the vascular levelcould also contribute to their beneficial effects.

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