title: Myeloperoxidase upregulates endothelin receptor type B expression.
abstract: Neutrophil recruitment and activation are principal events in inflammation. Upon activation neutrophils release myeloperoxidase (MPO), a heme enzyme, which binds to and transcytoses endothelial cells. Whereas the significance of the subendothelial deposition of MPO has evolved as a critical prerequisite for the enzyme's suppression of nitric oxide (NO⋅) bioavailability, the functional consequences of MPO binding to and interaction with endothelial and smooth muscle cells remain poorly understood. Cultured human endothelial cells (HUVECs) were exposed to MPO. Gene expression of the endothelin receptor type B (ETRB), which is critically involved not only in endothelin-1 clearance, but also in endothelin-mediated vasoconstriction, was significantly increased. Real time PCR, Western blotting and immunofluorescence confirmed up-regulation of ETRB in MPO-treated endothelial cells. Inhibition of MPO's enzymatic activity blunted the increase in ETRB protein expression. Treatment of the cells with the MAP kinase inhibitors PD98059 or SB203580 indicates that MPO activates ETRB expression via MAP kinase pathways. On human smooth muscle cells (HAoSMCs), which not only express the endothelin receptor type B (ETRB) but also express the endothelin receptor type A (ETRA), MPO also stimulated ETRB expression as opposed to ETRA expression, which remained unchanged. Functional ex vivo organ bath chamber studies with MPO-incubated rat femoral artery sections revealed increased ETRB agonist dependent constriction. Binding of MPO to endothelial and vascular smooth muscle cells increases expression of the endothelin receptor type B (ETRB) via classical MAP kinase pathways. This suggests that MPO not only affects vasomotion by reducing the bioavailability of vasodilating molecules but also by increasing responsiveness to vasoconstrictors, further advocating for MPO as a central, leukocyte-derived regulator of vascular tone.
authors.affiliation: Cardiovascular Research Center, University Heart Center Hamburg, University Hospital Eppendorf, Martinistreet 52, 20246 Hamburg, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Lau
authors.affiliation: Cardiovascular Research Center, University Heart Center Hamburg, University Hospital Eppendorf, Martinistreet 52, 20246 Hamburg, Germany.
authors.forename: Katalin
authors.initials: K
authors.lastname: Szöcs
authors.affiliation: Cardiology, Heart Center, University Hospital Cologne, Kerpener Street 62, 50937 Cologne, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
authors.affiliation: Cardiology, Heart Center, University Hospital Cologne, Kerpener Street 62, 50937 Cologne, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Rudolph
authors.affiliation: Cardiology, Heart Center, University Hospital Cologne, Kerpener Street 62, 50937 Cologne, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.affiliation: Institute of Clinical Chemistry, University Hospital Eppendorf, Martinistreet 52, 20246 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.affiliation: Cardiovascular Research Center, University Heart Center Hamburg, University Hospital Eppendorf, Martinistreet 52, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: Cardiology, Heart Center, University Hospital Cologne, Kerpener Street 62, 50937 Cologne, Germany. Electronic address: stephan.baldus@uk-koeln.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D009195:Peroxidase
keywords: Endothelial cells; Endothelin receptor type B; Myeloperoxidase; Smooth muscle cells; Vasomodulation