title: Cytoprotective gene HO-1 and chronic rejection in heart transplantation.
abstract: Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. We hypothesized that induction of HO-1 by D4-F, an apoA-I mimetic peptide with potent antiinflammatory/antioxidant properties, attenuated CAV. We utilized a previously characterized murine model of CAV. B6.C-H2(bml2) hearts were heterotopically transplanted into C57BL/6 mice. In the control group, recipient mice were treated with 20 microg of saline daily. In experimental group I, mice were treated daily with 20 microg of D4-F. In experimental group II, mice were treated daily with 20 microg of D4-F daily, plus CuPP, which does not have any effect on HO-1 activity. In experimental group III, recipient mice were treated with 20 mug of D4-F daily, plus SnPP, which is a competitive inhibitor of HO-1. Donor hearts were harvested on day 24 after transplantation. The donor hearts in the control group developed severe intimal lesions. In experimental group I, treatment with D4-F was associated with upregulation of HO-1 and a marked reduction in intimal lesions, which was consistent in experimental group II. In experimental group III, inhibition of HO-1 was associated with partial restoration of intimal lesions. Induction of HO-1 by an apoA-1 mimetic peptide was effective to control CAV. This class of antiinflammatory peptides, which show an ability to induce HO-1, provides a novel strategy for the treatment of CAV.
authors.affiliation: Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. gschnickel@mednet.ucla.edu
authors.forename: G T
authors.initials: GT
authors.lastname: Schnickel
authors.forename: G R
authors.initials: GR
authors.lastname: Hsieh
authors.forename: E L
authors.initials: EL
authors.lastname: Kachikwu
authors.forename: C
authors.initials: C
authors.lastname: Garcia
authors.forename: A
authors.initials: A
authors.lastname: Shefizadeh
authors.forename: M C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: A
authors.initials: A
authors.lastname: Ardehali
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000494:pharmacology; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010446:Peptide Fragments / Q000494:pharmacology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D010446:Peptide Fragments; D051547:Heme Oxygenase-1