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@ARTICLE{Dangwal:14547,
author = {Dangwal, S. and Rauch, B.H. and Gensch, T. and Dai, L. and
Bretschneider, E. and Vogelaar, C.F. and Schrör, K. and
Rosenkranz, A.C.},
title = {{H}igh glucose enhances thrombin responses via
protease-activated receptor-4 in human vascular smooth
muscle cells},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {31},
issn = {1079-5642},
address = {Philadelphia, Pa.},
publisher = {Lippincott, Williams $\&$ Wilkins},
reportid = {PreJuSER-14547},
pages = {624 - 633},
year = {2011},
note = {This study was supported in part by the Deutsche
Forschungsgemeinschaft (SFB 612, Project B11), the Anna
Wunderlich-Ernst Juhling Stiftung (Dusseldorf, Germany), and
the Forschungsgruppe Herz-Kreislauf eV (Monheim, Germany).},
abstract = {Diabetes is associated with vascular remodeling and
increased thrombin generation. Thrombin promotes vascular
smooth muscle cell (SMC) mitogenesis and migration via
protease-activated receptors (PAR)-1, PAR-3, and PAR-4. We
investigated the effect of high glucose on expression and
function of vascular thrombin receptors.In human vascular
SMCs, high glucose (25 versus 5.5 mmol/L) induced a rapid
and sustained increase in PAR-4 mRNA, protein, and cell
surface expression. PAR-1 and PAR-3 expression were not
changed. High glucose pretreatment (48 hours) enhanced
thrombin or PAR-4-activating peptide but not
PAR-1-activating peptide evoked intracellular calcium
mobilization, migration, and tumor necrosis factor α gene
expression. This enhancement of thrombin-stimulated
migration and gene expression by high glucose was abolished
by endogenous PAR-4 knockdown. PAR-4 regulation was
prevented by inhibition of protein kinase (PK)C-β and -δ
isoforms or nuclear factor (NF)κB. Nuclear translocation of
NFκB in high glucose-stimulated SMCs led to PKC-dependent
NFκB binding to the PAR-4 promoter in a chromatin
immunoprecipitation assay. Furthermore, in situ
hybridization and immunohistochemistry confirmed high
abundance of PAR-4 in human diabetic vessels as compared
with nondiabetic vessels.High glucose enhances SMC
responsiveness to thrombin through transcriptional
upregulation of PAR-4, mediated via PKC-β, -δ, and NFκB.
This may play an important role in the vascular
complications of diabetes.},
keywords = {Binding Sites / Calcium: metabolism / Calcium Signaling /
Cell Movement / Cells, Cultured / Chromatin
Immunoprecipitation / Diabetic Angiopathies: genetics /
Diabetic Angiopathies: metabolism / Glucose: metabolism /
Humans / Immunohistochemistry / In Situ Hybridization /
Muscle, Smooth, Vascular: metabolism / Myocytes, Smooth
Muscle: metabolism / NF-kappa B: metabolism / Promoter
Regions, Genetic / Protein Kinase C: antagonists $\&$
inhibitors / Protein Kinase C: metabolism / Protein Kinase
C-delta: genetics / Protein Kinase C-delta: metabolism /
Protein Kinase Inhibitors: pharmacology / RNA Interference /
RNA, Messenger: metabolism / Receptor, PAR-1: metabolism /
Receptors, Thrombin: genetics / Receptors, Thrombin:
metabolism / Thrombin: metabolism / Time Factors /
Transcriptional Activation / Tumor Necrosis Factor-alpha:
genetics / Up-Regulation / NF-kappa B (NLM Chemicals) /
Protein Kinase Inhibitors (NLM Chemicals) / RNA, Messenger
(NLM Chemicals) / Receptor, PAR-1 (NLM Chemicals) /
Receptors, Thrombin (NLM Chemicals) / Tumor Necrosis
Factor-alpha (NLM Chemicals) / protease-activated receptor 3
(NLM Chemicals) / protease-activated receptor 4 (NLM
Chemicals) / Glucose (NLM Chemicals) / Calcium (NLM
Chemicals) / protein kinase C beta (NLM Chemicals) / PRKCD
protein, human (NLM Chemicals) / Protein Kinase C (NLM
Chemicals) / Protein Kinase C-delta (NLM Chemicals) /
Thrombin (NLM Chemicals) / J (WoSType)},
cin = {ISB-1},
ddc = {610},
cid = {I:(DE-Juel1)VDB922},
pnm = {BioSoft: Makromolekulare Systeme und biologische
Informationsverarbeitung},
pid = {G:(DE-Juel1)FUEK505},
shelfmark = {Hematology / Peripheral Vascular Disease},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:21164077},
UT = {WOS:000287409900023},
doi = {10.1161/ATVBAHA.110.219105},
url = {https://juser.fz-juelich.de/record/14547},
}