TY  - JOUR
AU  - Dangwal, S.
AU  - Rauch, B.H.
AU  - Gensch, T.
AU  - Dai, L.
AU  - Bretschneider, E.
AU  - Vogelaar, C.F.
AU  - Schrör, K.
AU  - Rosenkranz, A.C.
TI  - High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells
JO  - Arteriosclerosis, thrombosis, and vascular biology
VL  - 31
SN  - 1079-5642
CY  - Philadelphia, Pa.
PB  - Lippincott, Williams & Wilkins
M1  - PreJuSER-14547
SP  - 624 - 633
PY  - 2011
N1  - 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).
AB  - 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.
KW  - Binding Sites
KW  - Calcium: metabolism
KW  - Calcium Signaling
KW  - Cell Movement
KW  - Cells, Cultured
KW  - Chromatin Immunoprecipitation
KW  - Diabetic Angiopathies: genetics
KW  - Diabetic Angiopathies: metabolism
KW  - Glucose: metabolism
KW  - Humans
KW  - Immunohistochemistry
KW  - In Situ Hybridization
KW  - Muscle, Smooth, Vascular: metabolism
KW  - Myocytes, Smooth Muscle: metabolism
KW  - NF-kappa B: metabolism
KW  - Promoter Regions, Genetic
KW  - Protein Kinase C: antagonists & inhibitors
KW  - Protein Kinase C: metabolism
KW  - Protein Kinase C-delta: genetics
KW  - Protein Kinase C-delta: metabolism
KW  - Protein Kinase Inhibitors: pharmacology
KW  - RNA Interference
KW  - RNA, Messenger: metabolism
KW  - Receptor, PAR-1: metabolism
KW  - Receptors, Thrombin: genetics
KW  - Receptors, Thrombin: metabolism
KW  - Thrombin: metabolism
KW  - Time Factors
KW  - Transcriptional Activation
KW  - Tumor Necrosis Factor-alpha: genetics
KW  - Up-Regulation
KW  - NF-kappa B (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Receptor, PAR-1 (NLM Chemicals)
KW  - Receptors, Thrombin (NLM Chemicals)
KW  - Tumor Necrosis Factor-alpha (NLM Chemicals)
KW  - protease-activated receptor 3 (NLM Chemicals)
KW  - protease-activated receptor 4 (NLM Chemicals)
KW  - Glucose (NLM Chemicals)
KW  - Calcium (NLM Chemicals)
KW  - protein kinase C beta (NLM Chemicals)
KW  - PRKCD protein, human (NLM Chemicals)
KW  - Protein Kinase C (NLM Chemicals)
KW  - Protein Kinase C-delta (NLM Chemicals)
KW  - Thrombin (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:21164077
UR  - <Go to ISI:>//WOS:000287409900023
DO  - DOI:10.1161/ATVBAHA.110.219105
UR  - https://juser.fz-juelich.de/record/14547
ER  -