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(Circulation Research. 2008;102:59.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Hydrogen Peroxide Inhibits Cytochrome P450 Epoxygenases

Interaction Between Two Endothelium-Derived Hyperpolarizing Factors

Brandon T. Larsen, David D. Gutterman, Atsushi Sato, Kazuyoshi Toyama, William B. Campbell, Darryl C. Zeldin, Vijay L. Manthati, John R. Falck, Hiroto Miura

From the Departments of Pharmacology & Toxicology (B.T.L., D.D.G., W.B.C.) and Medicine (D.D.G., A.S., K.T., H.M.), Medical College of Wisconsin, Milwaukee; and Veterans Administration Medical Center (D.D.G.), Milwaukee, Wis; National Institute of Environmental Health Sciences (D.C.Z.), Research Triangle Park, NC; and Department of Biochemistry (V.L.M., J.R.F.), University of Texas Southwestern, Dallas.

Correspondence to Hiroto Miura, MD PhD, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail hmiura{at}mcw.edu

The cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic acid the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H₂O₂) both function as endothelium-derived hyperpolarizing factors (EDHFs) in the human coronary microcirculation. However, the relative importance of and potential interactions between these 2 vasodilators remain unexplored. We identified a novel inhibitory interaction between CYPs and H₂O₂ in human coronary arterioles, where EDHF-mediated vasodilatory mechanisms are prominent. Bradykinin induced vascular superoxide and H₂O₂ production in an endothelium-dependent manner and elicited a concentration-dependent dilation that was reduced by catalase but not by 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE), 6-(2-propargyloxyphenyl)hexanoic acid, sulfaphenazole, or iberiotoxin. However, in the presence of catalase, an inhibitory effect of these compounds was unmasked. In a tandem-bioassay preparation, application of bradykinin to endothelium-intact donor vessels elicited dilation of downstream endothelium-denuded detectors that was partially inhibited by donor-applied catalase but not by detector-applied EEZE; however, EEZE significantly inhibited dilation in the presence of catalase. EET production by human recombinant CYP 2C9 and 2J2, 2 major epoxygenase isozymes expressed in human coronary arterioles, was directly inhibited in a concentration-dependent fashion by H₂O₂ in vitro, as observed by high-performance liquid chromatography (HPLC); however, EETs were not directly sensitive to oxidative modification. H₂O₂ inhibited dilation to arachidonic acid but not to 11,12-EET. These findings suggest that an inhibitory interaction exists between 2 EDHFs in the human coronary microcirculation. CYP epoxygenases are directly inhibited by H₂O₂, and this interaction may modulate vascular EET bioavailability.

Key Words: endothelium-derived hyperpolarizing factor • hydrogen peroxide • epoxyeicosatrienoic acid • cytochrome P450 • reactive oxygen species

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