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Free radical biology & medicine 2013 Feb 28. pii: S0891-5849(13)00089-0. doi: 10.1016/j.freeradbiomed.2013.02.025. [Epub ahead of print]

Nitroxyl (HNO) Suppresses Vascular Nox2 Oxidase Activity.

Miller, AA; Maxwell, KF; Chrissobolis, S; Bullen, ML; Biomed, B; Ku, JM; Silva, T Michael De; Selemidis, S; Hooker, EU; Drummond, GR; Sobey, CG; Kemp-Harper, BK

Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Melbourne, VIC 3800, Australia.

Nox2 oxidase activity underlies the oxidative stress and vascular dysfunction associated with several vascular-related diseases. We have reported that nitric oxide (NO.) decreases reactive oxygen species production by endothelial Nox2 oxidase. This study tested the hypothesis that nitroxyl (HNO), the redox sibling of NO., also suppresses vascular Nox2 oxidase activity. Specifically, we examined the influence of two well-characterized HNO donors, Angeli's salt and isopropylamine NONOate (IPA/NO), on Nox2 oxidase-dependent responses to angiotensin II (reactive oxygen species production and vasoconstriction) in mouse cerebral arteries. Angiotensin II (0.1μmol/L)-stimulated superoxide (measured by lucigenin-enhanced chemiluminescence) and hydrogen peroxide (Amplex Red fluorescence) levels in cerebral arteries (pooled basilar and middle cerebral [MCA]) from wild-type (WT) mice were ~60% lower (PCA was virtually abolished by IPA/NO (1μmol/L), whereas constrictor responses to either the thromboxane A2 mimetic U46619 (1-100nmol/L) or high potassium (122.7mmol/L) were unaffected. In conclusion, HNO suppresses vascular Nox2 oxidase activity via a sGC-cGMP-independent pathway. Thus, HNO donors might be useful therapeutic agents to limit and/or prevent Nox2 oxidase-dependent vascular dysfunction.

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