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Autocrine/paracrine pattern of superoxide production through NAD(P)H oxidase in coronary arterial myocytes

¹Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia; ²Section of Cardiology, Department of Medicine, Division of Biological Sciences and Pritzker School of Medicine, University of Chicago, Chicago, Illinois; ³ Research Center of Experimental Medicine, Guangxi Autonomous Region People's Hospital, Nanning, Guangxi, People's Republic of China

Submitted 14 June 2006 ; accepted in final form 31 August 2006

The present study tested the hypothesis that membrane-bound NAD(P)H oxidase in coronary arterial myocytes (CAMs) is capable of producing superoxide (O₂^–) toward extracellular space to exert an autocrine- or paracrine-like action in these cells. Using a high-speed wavelength-switching fluorescent microscopic imaging technique, we simultaneously monitored the binding of dihydroethidium-oxidizing product to exogenous salmon testes DNA trapped outside CAMs and to nuclear DNA as indicators of extra- and intracellular O₂^– production. It was found that a muscarinic agonist oxotremorine (OXO; 80 µM) increased O₂^– levels more rapidly outside than inside CAMs. In the presence of superoxide dismutase (500 U/ml) plus catalase (400 U/ml) and NAD(P)H oxidase inhibitor diphenylene iodonium (50 µM) or apocynin (100 µM), these increases in extra- and intracellular O₂^– levels were substantially abolished or attenuated. The O₂^– increase outside CAMs was also confirmed by detecting oxidation of nitro blue tetrazolium and confocal microscopic localization of Matrigel-trapped OxyBURST H₂HFF Green BSA staining around these cells. By electron spin resonance spectrometry, the extracellular accumulation of O₂^– was demonstrated as a superoxide dismutase-sensitive component outside CAMs. Furthermore, RNA interference of NAD(P)H oxidase subunits Nox1 or p47 markedly blocked OXO-induced increases in both extra- and intracellular O₂^– levels, whereas small inhibitory RNA of Nox4 only attenuated intracellular O₂^– accumulation. These results suggest that Nox1 represents a major NAD(P)H oxidase isoform responsible for extracellular O₂^– production. This rapid extracellular production of O₂^– seems to be unique to OXO-induced M₁-receptor activation, since ANG II-induced intra- and extracellular O₂^– increases in parallel. It is concluded that the outward production of O₂^– via NAD(P)H oxidase in CAMs may represent an important producing pattern for its autocrine or paracrine actions.

reactive oxygen species; redox signaling; artery

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