| First Author | Kinderlerer AR | Year | 2009 |
| Journal | Blood | Volume | 113 |
| Issue | 7 | Pages | 1598-607 |
| PubMed ID | 19036700 | Mgi Jnum | J:145551 |
| Mgi Id | MGI:3835223 | Doi | 10.1182/blood-2008-04-152934 |
| Citation | Kinderlerer AR, et al. (2009) 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. Blood 113(7):1598-607 |
| abstractText | 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. |
