%0 Journal Article
%A Dangwal, S.
%A Rauch, B.H.
%A Gensch, T.
%A Dai, L.
%A Bretschneider, E.
%A Vogelaar, C.F.
%A Schrör, K.
%A Rosenkranz, A.C.
%T High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells
%J Arteriosclerosis, thrombosis, and vascular biology
%V 31
%@ 1079-5642
%C Philadelphia, Pa.
%I Lippincott, Williams & Wilkins
%M PreJuSER-14547
%P 624 - 633
%D 2011
%Z 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).
%X 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.
%K Binding Sites
%K Calcium: metabolism
%K Calcium Signaling
%K Cell Movement
%K Cells, Cultured
%K Chromatin Immunoprecipitation
%K Diabetic Angiopathies: genetics
%K Diabetic Angiopathies: metabolism
%K Glucose: metabolism
%K Humans
%K Immunohistochemistry
%K In Situ Hybridization
%K Muscle, Smooth, Vascular: metabolism
%K Myocytes, Smooth Muscle: metabolism
%K NF-kappa B: metabolism
%K Promoter Regions, Genetic
%K Protein Kinase C: antagonists & inhibitors
%K Protein Kinase C: metabolism
%K Protein Kinase C-delta: genetics
%K Protein Kinase C-delta: metabolism
%K Protein Kinase Inhibitors: pharmacology
%K RNA Interference
%K RNA, Messenger: metabolism
%K Receptor, PAR-1: metabolism
%K Receptors, Thrombin: genetics
%K Receptors, Thrombin: metabolism
%K Thrombin: metabolism
%K Time Factors
%K Transcriptional Activation
%K Tumor Necrosis Factor-alpha: genetics
%K Up-Regulation
%K NF-kappa B (NLM Chemicals)
%K Protein Kinase Inhibitors (NLM Chemicals)
%K RNA, Messenger (NLM Chemicals)
%K Receptor, PAR-1 (NLM Chemicals)
%K Receptors, Thrombin (NLM Chemicals)
%K Tumor Necrosis Factor-alpha (NLM Chemicals)
%K protease-activated receptor 3 (NLM Chemicals)
%K protease-activated receptor 4 (NLM Chemicals)
%K Glucose (NLM Chemicals)
%K Calcium (NLM Chemicals)
%K protein kinase C beta (NLM Chemicals)
%K PRKCD protein, human (NLM Chemicals)
%K Protein Kinase C (NLM Chemicals)
%K Protein Kinase C-delta (NLM Chemicals)
%K Thrombin (NLM Chemicals)
%K J (WoSType)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:21164077
%U <Go to ISI:>//WOS:000287409900023
%R 10.1161/ATVBAHA.110.219105
%U https://juser.fz-juelich.de/record/14547