Journal Article

PreJuSER-14547

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells

Dangwal, S. ; Rauch, B. H. ; Gensch, T.FZJ* ; Dai, L.FZJ* ; Bretschneider, E. ; Vogelaar, C. F. ; Schrör, K. ; Rosenkranz, A. C.

2011
Lippincott, Williams & Wilkins Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1161/ATVBAHA.110.219105

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.

Keyword(s): Binding Sites (MeSH) ; Calcium: metabolism (MeSH) ; Calcium Signaling (MeSH) ; Cell Movement (MeSH) ; Cells, Cultured (MeSH) ; Chromatin Immunoprecipitation (MeSH) ; Diabetic Angiopathies: genetics (MeSH) ; Diabetic Angiopathies: metabolism (MeSH) ; Glucose: metabolism (MeSH) ; Humans (MeSH) ; Immunohistochemistry (MeSH) ; In Situ Hybridization (MeSH) ; Muscle, Smooth, Vascular: metabolism (MeSH) ; Myocytes, Smooth Muscle: metabolism (MeSH) ; NF-kappa B: metabolism (MeSH) ; Promoter Regions, Genetic (MeSH) ; Protein Kinase C: antagonists & inhibitors (MeSH) ; Protein Kinase C: metabolism (MeSH) ; Protein Kinase C-delta: genetics (MeSH) ; Protein Kinase C-delta: metabolism (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; RNA Interference (MeSH) ; RNA, Messenger: metabolism (MeSH) ; Receptor, PAR-1: metabolism (MeSH) ; Receptors, Thrombin: genetics (MeSH) ; Receptors, Thrombin: metabolism (MeSH) ; Thrombin: metabolism (MeSH) ; Time Factors (MeSH) ; Transcriptional Activation (MeSH) ; Tumor Necrosis Factor-alpha: genetics (MeSH) ; Up-Regulation (MeSH) ; NF-kappa B ; Protein Kinase Inhibitors ; RNA, Messenger ; Receptor, PAR-1 ; Receptors, Thrombin ; Tumor Necrosis Factor-alpha ; protease-activated receptor 3 ; protease-activated receptor 4 ; Glucose ; Calcium ; protein kinase C beta ; PRKCD protein, human ; Protein Kinase C ; Protein Kinase C-delta ; Thrombin ; J ; diabetes mellitus (auto) ; thrombin (auto) ; vascular muscle (auto) ; protease-activated receptors (auto)

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).

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Contributing Institute(s):

1. Zelluläre Biophysik (ISB-1)

Research Program(s):

1. BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung (P45)

Appears in the scientific report 2011

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