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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1598-1607. Prepublished online as a Blood First Edition Paper on November 25, 2008; DOI 10.1182/blood-2008-04-152934. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-04-152934v1 113/7/1598    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kinderlerer, A. R Articles by Mason, J. C Search for Related Content PubMed PubMed Citation Articles by Kinderlerer, A. R Articles by Mason, J. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 18, 2008 Accepted November 12, 2008 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 Anne R Kinderlerer, Isabel Pombo Gregoire, Shahir S Hamdulay, Faisal Ali, Rivka Steinberg, Gabriela Silva, Nadira Ali, Bufei Wang, Dorian O Haskard, Miguel P Soares, and Justin C Mason* The Bywaters Centre for Vascular Inflammation, Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, United Kingdom Instituto Gulbenkian de Ciencia, Oeiras, Portugal * Corresponding author; email: justin.mason{at}imperial.ac.uk. 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, anti-apoptotic, anti-proliferative and anti-oxidant effects. We have identified an additional cytoprotective action, the regulation of complement activation, mediated via induction of decay-accelerating factor (DAF). Pharmacological inhibition or siRNA depletion of HO-1 prevented induction of DAF expression in human endothelial cells (EC). 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 over-expression of HO-1 increased DAF expression, enhancing protection against C3 deposition and complement-mediated lysis, and this was reversed by DAF inhibitory mAb 1H4. Likewise, bilirubin, Fe chelation or over-expression of heavy chain ferritin all induced DAF expression in EC. Analysis of cardiac EC isolated from Hmox1-/- mice revealed a 60% reduction in DAF expression as compared to 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 post-transplant vasculopathy, allograft rejection and ischemia-reperfusion. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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