on June 22, 2006
Published online before print June 22, 2006, doi: 10.1161/01.ATV.0000233334.24805.62
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Submitted on December 10, 2005
Accepted on June 9, 2006
Upregulation of Arginase by H2O2 Impairs Endothelium-Dependent Nitric Oxide-Mediated Dilation of Coronary Arterioles
Naris Thengchaisri ;
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.
* To whom correspondence should be addressed. 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.
Key words: endothelium • free radicals • hydrogen peroxide • nitric oxide
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