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

Hendry Saragih; Eva Zilian; Yarúa Jaimes; Ananta Paine; Constanca Figueiredo; Britta Eiz-Vesper; Rainer Blasczyk; Jan Larmann; Gregor Theilmeier; Monika Burg-Roderfeld; Luminita-Cornelia Andrei-Selmer; Jan Ulrich Becker; Sentot Santoso; Stephan Immenschuh

doi:10.1160/TH13-11-0923

Thrombosis and Haemostasis, Table of Contents

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

Authors

Hendry Saragih^*

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

²Faculty of Biology, Gadjah Mada University, Yogyakarta, Indonesia
Eva Zilian^*

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

⁷Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
Yarúa Jaimes

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
Ananta Paine

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
Constanca Figueiredo

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
Britta Eiz-Vesper

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

⁷Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany
Rainer Blasczyk

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany
Jan Larmann

⁴Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
Gregor Theilmeier

⁴Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
Monika Burg-Roderfeld

⁵Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University, Giessen, Germany
Luminita-Cornelia Andrei-Selmer

⁶Institute of Anatomy, University of Bonn, Germany;
Jan Ulrich Becker

³Institute for Pathology, Hannover Medical School, Hannover, Germany
Sentot Santoso

⁵Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University, Giessen, Germany
Stephan Immenschuh

¹Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany

⁷Integrated Research and Treatment Center (IFB-Tx), Hannover Medical School, Hannover, Germany

Abstract

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

Full Text

References

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