Published Online
on August 6, 2007

A more recent version of this article appeared on October 1, 2007

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Submitted on April 10, 2007
Revised on May 8, 2007

Induction of Heme Oxygenase-1 In Vivo Suppresses NADPH Oxidase–Derived Oxidative Stress

Srinivasa R. Datla; Gregory J. Dusting; Trevor A. Mori; Caroline J. Taylor; Kevin D. Croft; and Fan Jiang^*

From the Bernard O'Brien Institute of Microsurgery (S.R.D., G.J.D., C.J.T., F.J.), University of Melbourne, Victoria, Australia; and the School of Medicine and Pharmacology (T.A.M., K.D.C.), University of Western Australia, Western Australia, Australia.

^* To whom correspondence should be addressed. E-mail: fjiang{at}unimelb.edu.au.

Abstract—Our previous stgips suggest that heme oxygenase (HO)-1 induction and/or subsequent bilirubin generation in endothelial cells may suppress superoxide generation of from reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. In this study, we examined the consequence of HO-1 induction in vivo on NADPH oxidase activity. Three doses of hemin (25 mg · kg^-1, IP, every 48 hours), with or without cotreatment with the HO inhibitor tin protoporphyrin-IX (15 mg · kg^-1, IP), were given to apolipoprotein E–deficient mice, which display vascular oxidative stress. Hemin treatment increased HO-1 expression and activity in aorta (undetectable at baseline) and kidney (by 3-fold) and significantly reduced both NADPH oxidase activity (by 25% to 50%) and superoxide generation in situ. The increase in HO-1 activity and inhibition of NADPH oxidase activity by hemin were reversed by tin protoporphyrin-IX and were not associated with changes in Nox2 or Nox4 protein levels. Hemin also reduced plasma F₂-isoprostane levels by 23%. The inhibition of NADPH oxidase activity by hemin in the aorta was mimicked by bilirubin in vitro (0.01 to 1 µmol/L). Bilirubin also concentration-dependently reduced NADPH oxidase–dependent superoxide production stimulated by angiotensin II in rat vascular smooth muscle cells and by phorbol 12-myristate 13-acetate in human neutrophil-like HL-60 cells. HO-1 overexpression by plasmid-mediated gene transfer in rat vascular smooth muscle cells decreased NADPH-stimulated superoxide production. Thus, systemic expression of HO-1 suppresses NADPH oxidase activity by mechanisms at least partly mediated by the bile pigment bilirubin, thereby reducing oxidative stress.

Key words: bilirubin • heme oxygenase-1 • NADPH oxidase • oxidative stress • reactive oxygen species

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