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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 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 Citation Map 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  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY 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. Kinderlerer1, Isabel Pombo Gregoire2,*, Shahir S. Hamdulay1,*, Faisal Ali1, Rivka Steinberg1, Gabriela Silva2, Nadira Ali1, Bufei Wang1, Dorian O. Haskard1, Miguel P. Soares2, and Justin C. Mason1 1 Bywaters Center for Vascular Inflammation, Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and 2 Instituto Gulbenkian de Ciência, Oeiras, Portugal 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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