期刊
BLOOD
卷 113, 期 7, 页码 1598-1607出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-04-152934
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资金
- Arthritis Research Campaign [KO566, 13616]
- European Community, 6th Framework [LSH-2005-1.2.5-1]
- Phillip Morris External Research Program [POCTI/SAU-MNO/56066/2004, POCTI/BIABCM/56829/2004]
- Fundacao para a Ciencia e Tecnologia (Lisbon, Portugal)
- Fundacaopara a Ciencia e Tecnologia (Lisbon, Portugal) [SFRH/BPD/9380/2002, SFRH/BPD/21072/2004]
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/21072/2004, SFRH/BPD/9380/2002] Funding Source: FCT
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, antiapoptotic, 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. (Blood. 2009; 113: 1598-1607)
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