title: Heme oxygenase-1 expression enhances vascular endothelial resistance to complement-mediated injury through induction of decay-accelerating factor: a role for increased bilirubin and ferritin.
abstract: Catabolism of free heme by heme oxygenase-1 (HO-1) generates carbon monoxide, biliverdin, and free iron (Fe). These end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, antiapo-ptotic, antiproliferative, and antioxidant effects. We have identified an additional cytoprotective action, the regulation of complement activation, mediated via induction of decay-accelerating factor (DAF). Pharmacologic inhibition or short-interfering RNA (siRNA) depletion of HO-1 prevented induction of DAF expression in human endothelial cells. In contrast, HO-1 agonists hemin and cobalt protoporphyrin IX significantly increased DAF protein expression, reflecting an increase in transcription and steady-state mRNA. Adenoviral-mediated overexpression of HO-1 increased DAF expression, enhancing protection against C3 deposition and complement-mediated lysis, and this was reversed by DAF inhibitory monoclonal antibody (mAb) 1H4. Likewise, bilirubin, Fe chelation, and overexpression of heavy-chain ferritin all induced DAF expression in endothelial cells (EC). Analysis of cardiac endothelial cells isolated from Hmox1(-/-) mice revealed a 60% reduction in DAF expression compared with Hmox1(+/+) EC, and Hmox1(-/-) cells showed enhanced sensitivity to complement. We propose that modulation of complement activation through induction of DAF represents an important component of the cytoprotective effects of HO-1 against vascular injury, such as that associated with posttransplant vasculopathy, allograft rejection, and ischemia reperfusion.
authors.affiliation: Bywaters Center for Vascular Inflammation, Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Kinderlerer
authors.forename: Isabel
authors.initials: I
authors.lastname: Pombo Gregoire
authors.forename: Shahir S
authors.initials: SS
authors.lastname: Hamdulay
authors.forename: Faisal
authors.initials: F
authors.lastname: Ali
authors.forename: Rivka
authors.initials: R
authors.lastname: Steinberg
authors.forename: Gabriela
authors.initials: G
authors.lastname: Silva
authors.forename: Nadira
authors.initials: N
authors.lastname: Ali
authors.forename: Bufei
authors.initials: B
authors.lastname: Wang
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000378:metabolism*; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D003165:Complement System Proteins / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D014652:Vascular Diseases / Q000276:immunology / Q000378:metabolism
chemical_list: D018958:CD55 Antigens; D008565:Membrane Proteins; D011524:Protoporphyrins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C521184:decay-accelerating factor 1, mouse; D003165:Complement System Proteins; D005293:Ferritins; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001663:Bilirubin