This title appears in the Scientific Report :
2011
Please use the identifier:
http://dx.doi.org/10.1161/ATVBAHA.110.219105 in citations.
High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells
High glucose enhances thrombin responses via protease-activated receptor-4 in human vascular smooth muscle cells
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 vascul...
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Personal Name(s): | Dangwal, S. |
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Rauch, B.H. / Gensch, T. / Dai, L. / Bretschneider, E. / Vogelaar, C.F. / Schrör, K. / Rosenkranz, A.C. | |
Contributing Institute: |
Zelluläre Biophysik; ISB-1 |
Published in: | Arteriosclerosis, thrombosis, and vascular biology, 31 (2011) S. 624 - 633 |
Imprint: |
Philadelphia, Pa.
Lippincott, Williams & Wilkins
2011
|
Physical Description: |
624 - 633 |
DOI: |
10.1161/ATVBAHA.110.219105 |
PubMed ID: |
21164077 |
Document Type: |
Journal Article |
Research Program: |
BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung |
Series Title: |
Arteriosclerosis, Thrombosis, and Vascular Biology
31 |
Subject (ZB): | |
Publikationsportal JuSER |
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. |