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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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Subunit composition of the NADPH oxidase isoforms. The catalytic core subunits of the complex(NOX1–5 and DUOX1–2) are shown in grey and their stabilization partners (p22phox andDUOX activator 1 and 2) are shown in magenta. NOX4 is the only isoform that produces hydrogenperoxide instead of superoxide anion. The regulatory cytosolic subunits of each isoform are shown ineach case: p40phox, p47phox, p67phox, NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), small GTPase(Rac), polymerase delta-interacting protein 2 (POLDIP2), a p47phox analog tyrosine kinase substratewith 4/5 SH3 domains (TKS4/5), EF hand motifs, (calcium-binding motifs composed of two helixes (Eand F) joined by a loop), calmodulin (CaM) and heat shock protein 90 (HSP90). On DUXO1 and DUOX2 aputative additional amino-terminal transmembrane domain and extracellular peroxidase-like region(PLD) are shown.Abbreviations: C-ter, carboxy-terminal; FAD, flavin adenine dinucleotide; GTPase,guanine triphosphate hydrolase; NADPH, nicotinamide adenine dinucleotide phosphate; N-ter,amino-terminal; O2, oxygen; H2O2, hydrogen peroxide;O2−, superoxide; SH3, Src-homology region 3.
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f2-vhrm-9-401: Subunit composition of the NADPH oxidase isoforms. The catalytic core subunits of the complex(NOX1–5 and DUOX1–2) are shown in grey and their stabilization partners (p22phox andDUOX activator 1 and 2) are shown in magenta. NOX4 is the only isoform that produces hydrogenperoxide instead of superoxide anion. The regulatory cytosolic subunits of each isoform are shown ineach case: p40phox, p47phox, p67phox, NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), small GTPase(Rac), polymerase delta-interacting protein 2 (POLDIP2), a p47phox analog tyrosine kinase substratewith 4/5 SH3 domains (TKS4/5), EF hand motifs, (calcium-binding motifs composed of two helixes (Eand F) joined by a loop), calmodulin (CaM) and heat shock protein 90 (HSP90). On DUXO1 and DUOX2 aputative additional amino-terminal transmembrane domain and extracellular peroxidase-like region(PLD) are shown.Abbreviations: C-ter, carboxy-terminal; FAD, flavin adenine dinucleotide; GTPase,guanine triphosphate hydrolase; NADPH, nicotinamide adenine dinucleotide phosphate; N-ter,amino-terminal; O2, oxygen; H2O2, hydrogen peroxide;O2−, superoxide; SH3, Src-homology region 3.

Mentions: Seven isoforms of NADPH oxidase have been described in mammals. Each of these isoforms comprisesa core catalytic subunit, ie, the so-called NADPH oxidase (NOX) and dual oxidase (DUOX) subunits,and up to five regulatory subunits. These regulatory subunits have important roles in: maturationand expression of the NOX and DUOX subunits in biological membranes, (ie, p22phox, DUOX activator 1,and DUOX activator 2), in enzyme activation (p67phox and NOX activator 1), and in spatialorganization of the various components of the enzyme complex (p47phox, NOX organizer 1, andp40phox).20 Some NADPH oxidase isoforms also relyon the small guanine triphosphate hydrolases (GTPases), ie, RAC1 and RAC2, for their activation.Each NADPH oxidase isoform is defined by the nature of its catalytic subunit (NOX1–NOX5,DUOX1, or DUOX2), which determines its suit of regulatory subunits (Figure 2).


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)

Subunit composition of the NADPH oxidase isoforms. The catalytic core subunits of the complex(NOX1–5 and DUOX1–2) are shown in grey and their stabilization partners (p22phox andDUOX activator 1 and 2) are shown in magenta. NOX4 is the only isoform that produces hydrogenperoxide instead of superoxide anion. The regulatory cytosolic subunits of each isoform are shown ineach case: p40phox, p47phox, p67phox, NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), small GTPase(Rac), polymerase delta-interacting protein 2 (POLDIP2), a p47phox analog tyrosine kinase substratewith 4/5 SH3 domains (TKS4/5), EF hand motifs, (calcium-binding motifs composed of two helixes (Eand F) joined by a loop), calmodulin (CaM) and heat shock protein 90 (HSP90). On DUXO1 and DUOX2 aputative additional amino-terminal transmembrane domain and extracellular peroxidase-like region(PLD) are shown.Abbreviations: C-ter, carboxy-terminal; FAD, flavin adenine dinucleotide; GTPase,guanine triphosphate hydrolase; NADPH, nicotinamide adenine dinucleotide phosphate; N-ter,amino-terminal; O2, oxygen; H2O2, hydrogen peroxide;O2−, superoxide; SH3, Src-homology region 3.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3750863&req=5

f2-vhrm-9-401: Subunit composition of the NADPH oxidase isoforms. The catalytic core subunits of the complex(NOX1–5 and DUOX1–2) are shown in grey and their stabilization partners (p22phox andDUOX activator 1 and 2) are shown in magenta. NOX4 is the only isoform that produces hydrogenperoxide instead of superoxide anion. The regulatory cytosolic subunits of each isoform are shown ineach case: p40phox, p47phox, p67phox, NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), small GTPase(Rac), polymerase delta-interacting protein 2 (POLDIP2), a p47phox analog tyrosine kinase substratewith 4/5 SH3 domains (TKS4/5), EF hand motifs, (calcium-binding motifs composed of two helixes (Eand F) joined by a loop), calmodulin (CaM) and heat shock protein 90 (HSP90). On DUXO1 and DUOX2 aputative additional amino-terminal transmembrane domain and extracellular peroxidase-like region(PLD) are shown.Abbreviations: C-ter, carboxy-terminal; FAD, flavin adenine dinucleotide; GTPase,guanine triphosphate hydrolase; NADPH, nicotinamide adenine dinucleotide phosphate; N-ter,amino-terminal; O2, oxygen; H2O2, hydrogen peroxide;O2−, superoxide; SH3, Src-homology region 3.
Mentions: Seven isoforms of NADPH oxidase have been described in mammals. Each of these isoforms comprisesa core catalytic subunit, ie, the so-called NADPH oxidase (NOX) and dual oxidase (DUOX) subunits,and up to five regulatory subunits. These regulatory subunits have important roles in: maturationand expression of the NOX and DUOX subunits in biological membranes, (ie, p22phox, DUOX activator 1,and DUOX activator 2), in enzyme activation (p67phox and NOX activator 1), and in spatialorganization of the various components of the enzyme complex (p47phox, NOX organizer 1, andp40phox).20 Some NADPH oxidase isoforms also relyon the small guanine triphosphate hydrolases (GTPases), ie, RAC1 and RAC2, for their activation.Each NADPH oxidase isoform is defined by the nature of its catalytic subunit (NOX1–NOX5,DUOX1, or DUOX2), which determines its suit of regulatory subunits (Figure 2).

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