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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2035.)
© 2006 American Heart Association, Inc.

Vascular Biology

Upregulation of Arginase by H₂O₂ Impairs Endothelium-Dependent Nitric Oxide-Mediated Dilation of Coronary Arterioles

Naris Thengchaisri; Travis W. Hein; Wei Wang; Xin Xu; Zhenbo Li; Theresa W. Fossum; Lih Kuo

From the Department of Systems Biology and Translational Medicine (N.T., T.W.H., W.W., X.X., Z.L., L.K.), Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, Temple, Tex; Department of Small Animal Medicine and Surgery (T.W.F.), College of Veterinary Medicine, Texas A&M University, College Station, Tex. Current Address for Naris Thengchaisri: Faculty of Veterinary Medicine, Kasetsart University, 50 Paholyothin Road, Bangkhen, Bangkok, Thailand.

Correspondence to Lih Kuo, Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, Texas A&M University System Health Science Center, Temple, TX 76502. E-mail LKUO{at}tamu.edu

Objective— Overproduction of reactive oxygen species such as hydrogen peroxide (H₂O₂) has been implicated in various cardiovascular diseases. However, mechanism(s) underlying coronary vascular dysfunction induced by H₂O₂ is unclear. We studied the effect of H₂O₂ on dilation of coronary arterioles to endothelium-dependent and endothelium-independent agonists.

Methods and Results— Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. All vessels developed basal tone and dilated dose-dependently to activators of nitric oxide (NO) synthase (adenosine and ionomycin), cyclooxygenase (arachidonic acid), and cytochrome P450 monooxygenase (bradykinin). Intraluminal incubation of vessels with H₂O₂ (100 µmol/L, 60 minutes) did not alter basal tone but inhibited vasodilations to adenosine and ionomycin in a manner similar as that by NO synthase inhibitor L-NAME. H₂O₂ affected neither endothelium-dependent responses to arachidonic acid and bradykinin nor endothelium-independent dilation to sodium nitroprusside. The inhibited adenosine response was not reversed by removal of H₂O₂ but was restored by excess L-arginine. Inhibition of L-arginine consuming enzyme arginase by -difluoromethylornithine or N-hydroxy-nor-L-arginine also restored vasodilation. Administering deferoxamine, an inhibitor of hydroxyl radical production, prevented the H₂O₂-induced impairment of vasodilation to adenosine. Western blot and reverse-transcription polymerase chain reaction results indicated that arginase I was upregulated after treating vessels with H₂O₂.

Conclusions— H₂O₂ specifically impairs endothelium-dependent NO-mediated dilation of coronary microvessels by reducing L-arginine availability through upregulation of arginase. The formation of hydroxyl radicals from H₂O₂ may contribute to this process.

Overproduction of reactive oxygen species such as hydrogen peroxide (H₂O₂) has been implicated in various cardiovascular diseases. Treatment of isolated coronary arterioles with H₂O₂ specifically attenuated endothelium-dependent NO-mediated dilation through the upregulation of arginase. Activation of this pathway may contribute to vascular dysfunction associated with oxidative stress.

Key Words: endothelium • free radicals • hydrogen peroxide • nitric oxide

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Hydrogen Peroxide: Watery Fuel for Change in Vascular Biology

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