title: Systemic rather than local heme oxygenase-1 overexpression improves cardiac allograft outcomes in a new transgenic mouse.
abstract: Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, exhibits potent antioxidant and anti-inflammatory properties. We developed HO-1 transgenic (Tg) mice using a rat HO-1 genomic transgene under the control of the endogenous promoter. Transgene expression was demonstrated by RT-PCR in all studied tissues, and a modest HO-1 overexpression was documented by Western, ELISA, and enzyme activity assays. To assess the effect of local vs systemic HO-1 in the acute rejection response, we used Tg mice as organ donors or recipients of MHC-incompatible heart grafts. In the local HO-1 overexpression model, Tg allografts survived 10.5 +/- 0.7 days (n = 10), compared with 6.5 +/- 0.4 days (n = 6) for wild-type donor controls (p = 0.0001). In the systemic HO-1 overexpression model, Tg recipients maintained allografts for 26.8 +/- 3.4 days (n = 10), compared with 6.3 +/- 0.1 days (n = 12) in wild-type controls (p = 0.00009). Inhibition of HO activity by treatment with tin protoporphyrin blunted survival advantage in Tg mice and resulted in acute graft rejection (n = 3). Increased carboxyhemoglobin levels were consistently noted in Tg mice. Comparisons of grafts at day 4 indicated that HO-1 overexpression was inversely associated with vasculitis/inflammatory cell infiltrate in both models. Hearts transplanted into Tg recipients showed decreased CD4(+) lymphocyte infiltration and diminished immune activation, as judged by CD25 expression. Thus, although local and systemic HO-1 overexpression improved allograft outcomes, systemic HO-1 led to a more robust protection and resulted in a significant blunting of host immune activation. This Tg mouse provides a valuable tool to study mechanisms by which HO-1 exerts beneficial effects in organ transplantation.
authors.affiliation: Division of Cardiology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Araujo
authors.forename: Lingzhong
authors.initials: L
authors.lastname: Meng
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Tward
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.forename: Annie
authors.initials: A
authors.lastname: Lee
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Suhasini
authors.initials: S
authors.lastname: Iyer
authors.forename: Roland
authors.initials: R
authors.lastname: Buelow
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D005786:Gene Expression Regulation / Q000276:immunology; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D019076:Transgenes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D008565:Membrane Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse