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

S.R. Datla, G.J. Dusting, Trevor Mori, C.J. Taylor, Kevin Croft, F. Jiang

Research output: Contribution to journalArticlepeer-review

179 Citations (Scopus)


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 center dot kg(-1), IP, every 48 hours), with or without cotreatment with the HO inhibitor tin protoporphyrin-IX (15 mg center dot 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 approximate to 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 F-2-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 mu mol/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.
Original languageEnglish
Pages (from-to)636-642
Publication statusPublished - 2007


Dive into the research topics of 'Induction of Heme Oxygenase-1 In Vivo Suppresses NADPH Oxidase-Derived Oxidative Stress'. Together they form a unique fingerprint.

Cite this