PECAM-1-dependent heme oxygenase-1 regulation via an Nrf2-mediated pathway in endothelial cells.
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.
Hendry
H
Saragih
Eva
E
Zilian
Yarúa
Y
Jaimes
Ananta
A
Paine
Constanca
C
Figueiredo
Britta
B
Eiz-Vesper
Rainer
R
Blasczyk
Jan
J
Larmann
Gregor
G
Theilmeier
Monika
M
Burg-Roderfeld
Luminita-Cornelia
LC
Andrei-Selmer
Jan Ulrich
JU
Becker
Sentot
S
Santoso
Dr. Stephan Immenschuh, Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany, Tel.: +49 511 532 6704, Fax: +49 511 532 2079, E-mail: Immenschuh.Stephan@mh-hannover.de.
Stephan
S
Immenschuh
D021581:Active Transport, Cell Nucleus; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007519:Isoantigens / Q000378:metabolism; D007739:L Cells; D051379:Mice; D053146:Myeloblastin / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
C407242:CD177 protein, human; D058851:GPI-Linked Proteins; D007519:Isoantigens; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D053146:Myeloblastin
Heme oxygenase-1; endothelial cells; inflammation; redox signalling; signal transduction