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(Hypertension. 2007;50:636.)
© 2007 American Heart Association, Inc.

Original Articles

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; 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.

Correspondence to Fan Jiang, Bernard O’Brien Institute of Microsurgery, 42 Fitzroy St, Fitzroy, Victoria 3065, Australia. E-mail fjiang{at}unimelb.edu.au

Our previous studies 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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