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Thromb Haemost 2014; 111(06): 1077-1088
DOI: 10.1160/TH13-11-0923
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

PECAM-1-dependent heme oxygenase-1 regulation via an Nrf2-mediated pathway in endothelial cells

Hendry Saragih   *
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
2   Faculty of Biology, Gadjah Mada University, Yogyakarta, Indonesia
,
Eva Zilian   *
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
7   Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
,
Yarúa Jaimes
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
,
Ananta Paine
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
,
Constanca Figueiredo
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
,
Britta Eiz-Vesper
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
7   Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
,
Rainer Blasczyk
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
,
Jan Larmann
4   Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
,
Gregor Theilmeier
4   Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
,
Monika Burg-Roderfeld
5   Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University, Giessen, Germany
,
Luminita-Cornelia Andrei-Selmer
6   Institute of Anatomy, University of Bonn, Germany;
,
Jan Ulrich Becker
3   Institute for Pathology, Hannover Medical School, Hannover, Germany
,
Sentot Santoso
5   Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University, Giessen, Germany
,
Stephan Immenschuh
1   Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
7   Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
› Author Affiliations Financial support: This work was supported by grants from the Deutsche Forschungsgemeinschaft [SFB547-A8 to SS and SI], the German Federal Ministry of Education and Research [Reference numbers 01E01302 to SI and ETB-0316045B to SI] and the Else Kröner- Fresenius Stiftung (EKFS 2012_A309).
Further Information

Publication History

Received: 11 November 2013

Accepted after minor revision: 07 January 2014

Publication Date:
02 December 2017 (online)

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Summary

The antioxidant enzyme heme oxygenase (HO)-1, which catalyses the first and rate-limiting step of heme degradation, has major anti-inflammatory and immunomodulatory effects via its cell-type-specific functions in the endothelium. In the current study, we investigated whether the key endothelial adhesion and signalling receptor PECAM-1 (CD31) might be involved in the regulation of HO-1 gene expression in human endothelial cells (ECs). To this end PECAM-1 expression was down-regulated in human umbilical vein ECs (HUVECs) by an adenoviral vector-based knockdown approach. PECAM-1 knockdown markedly induced HO-1, but not the constitutive HO isoform HO-2. Nuclear translocation of the transcription factor NF-E2-related factor-2 (Nrf2), which is a master regulator of the inducible antioxidant cell response, and intracellular levels of reactive oxygen species (ROS) were increased in PECAM-1-deficient HUVECs, respectively. PECAM-1-dependent HO-1 regulation was also examined in PECAM-1 over-expressing Chinese hamster ovary and murine L-cells. Endogenous HO-1 gene expression and reporter gene activity of transiently transfected luciferase HO-1 promoter constructs with Nrf2 target sequences were decreased in PECAM-1 over-expressing cells. Moreover, a regulatory role of ROS for HO-1 regulation in these cells is demonstrated by studies with the antioxidant N-acetylcysteine and exogenous hydrogenperoxide. Finally, direct interaction of PECAM-1 with a native complex of its binding partner NB1 (CD177) and serine proteinase 3 (PR3) from human neutrophils, markedly induced HO-1 expression in HUVECs. Taken together, we demonstrate a functional link between HO-1 gene expression and PECAM-1 in human ECs, which might play a critical role in the regulation of inflammation.

Keywords

Heme oxygenase-1 - redox signalling - inflammation - endothelial cells - signal transduction

* Equal contribution of these authors.


 

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