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.

journal_name

Blood

journal_title

Blood

authors

Kinderlerer AR,Pombo Gregoire I,Hamdulay SS,Ali F,Steinberg R,Silva G,Ali N,Wang B,Haskard DO,Soares MP,Mason JC

doi

10.1182/blood-2008-04-152934

subject

Has Abstract

pub_date

2009-02-12 00:00:00

pages

1598-607

issue

7

eissn

0006-4971

issn

1528-0020

pii

blood-2008-04-152934

journal_volume

113

pub_type

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