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Sulphonated aryls are novel selective inhibitors of Nox4‐dependent NADPH oxidase activity
Author(s) -
Drummond Grant R,
Dusting Gregory J,
Tan Chester SW,
Sobey Christopher G
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a725
Subject(s) - nadph oxidase , nox4 , chemistry , ic50 , antagonist , pharmacology , vascular smooth muscle , reactive oxygen species , biochemistry , suramin , superoxide , agonist , receptor , enzyme , in vitro , biology , endocrinology , smooth muscle
NADPH oxidases (Nox) are major sources of reactive oxygen species in blood vessels, and their upregulation underlies the oxidative stress associated with diseases such as hypertension. We recently showed that Nox4 is the predominant isoform expressed in vascular smooth muscle cells (VSMCs) and thus the aim of this study was to identify novel inhibitors of this enzyme. The pyridine nucleotide substrate for Nox, NADPH, displays agonist activity at P2 nucleotide receptors. Hence, we hypothesized that by analogy, P2 antagonists might display antagonist activity against Nox. NADPH caused concentration‐dependent increases in O 2 − production in mouse VSMC, as detected by lucigenin (pEC 50 , 4.8±0.1; R max , 9747±1751 cps/cell). Suramin, a sulphonated aryl and P2 antagonist, suppressed NADPH‐dependent O 2 − production in a concentration‐dependent fashion (IC 50 , 6.3±1.7μM), as did two structurally related compounds, reactive blue‐2 (IC 50 , 1.6±0.3μM) and PPADS (IC 50 , 3.6±0.9μM). In contrast, MRS 2179, a non‐sulphonated P2 antagonist, had no effect. Importantly, suramin was 50‐fold less potent at inhibiting Nox2‐dependent O 2 − production in J774 cells (IC 50 , ~300μM). In conclusion, this study is the first to identify a class of compounds that display selectivity for Nox4 over Nox2 and thus represents a platform for the design of novel therapeutics that selectively target vascular over phagocytic O 2 − production.