Nitroxyl (HNO) suppresses vascular Nox2 oxidase activity

Miller, A. A. et al. (2013) Nitroxyl (HNO) suppresses vascular Nox2 oxidase activity. Free Radical Biology and Medicine, 60, pp. 264-271. (doi: 10.1016/j.freeradbiomed.2013.02.025) (PMID:23459072)

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Abstract

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. 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-dependent responses to angiotensin II (reactive oxygen species production and vasoconstriction) in mouse cerebral arteries. Angiotensin II (0.1 μmol/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 (P<0.05) in the presence of either Angeli’s salt (1 μmol/L) or IPA/NO (1 μmol/L). Similarly, phorbyl 12,13-dibutyrate (10 μmol/L; Nox2 activator)-stimulated hydrogen peroxide levels were ~40% lower in the presence of IPA/NO (1 μmol/L; P<0.05). The ability of IPA/NO to decrease superoxide levels was reversible and abolished by the HNO scavenger l-cysteine (3 mmol/L; P<0.05), but was unaffected by hydroxocobalamin (100 μmol/L; NO scavenger), ODQ (10 μmol/L; soluble guanylyl cyclase (sGC) inhibitor), or Rp-8-pCPT-cGMPS (10 μmol/L; cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor). Angiotensin II-stimulated superoxide was substantially less in arteries from Nox2-deficient (Nox2−/y) versus WT mice (P<0.05). In contrast to WT, IPA/NO (1 μmol/L) had no effect on superoxide levels in arteries from Nox2−/y mice. Finally, angiotensin II (1–1000 μmol/L)-induced constriction of WT MCA was virtually abolished by IPA/NO (1 μmol/L), whereas constrictor responses to either the thromboxane A2 mimetic U46619 (1–100 nmol/L) or high potassium (122.7 mmol/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-dependent vascular dysfunction.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Dr Alyson
Authors: Miller, A. A., Maxwell, K. F., Chrissobolis, S., Bullen, M. L., Ku, J. M., Michael De Silva, T., Selemidis, S., Hooker, E. U., Drummond, G. R., Sobey, C. G., and Kemp-Harper, B. K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Free Radical Biology and Medicine
Publisher:Elsevier
ISSN:0891-5849
ISSN (Online):1873-4596
Published Online:28 February 2013

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