Dokument: High Glucose Regulation of Human Vascular Thrombin Receptor- Focus on PAR-4
| Titel: | High Glucose Regulation of Human Vascular Thrombin Receptor- Focus on PAR-4 | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=15646 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20100715-112211-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr. Dangwal, Seema [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Schrör, Karsten [Gutachter] Prof. Dr. Jose, Joachim [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Diabetes is clinically associated with enhanced thrombin generation, atherothrombosis and vascular remodeling. Clotting factor thrombin could modify these pathologies via protease-activated receptors- PAR-1, PAR-3 and PAR-4, exerting pleiotropic effects on vascular SMCs. This study investigates the possible regulation of thrombin receptors by high glucose in SMCs
Human saphenous vein SMCs were incubated under normal (5.5 mmol/L) or elevated (25 mmol/L) glucose conditions to investigate the influence on thrombin receptor expression, signaling and function. High glucose treatment selectively up regulated PAR-4 mRNA, protein and surface expression but not PAR-1 and PAR-3 expression in vascular SMCs. This regulation of PAR-4 was found to be independent of osmolar changes. Specific inhibitors of PKC-β or -δ or NF-κB prevented effect of high glucose on PAR-4 expression. Similar results were obtained from siRNA mediated silencing of PKC-δ or NF-κB in vascular SMCs. High glucose treatment induced NF-κB activation and translocation to the cell nucleus (maximal at 3 h pretreatment), where it could bind to the PAR-4 promoter, as demonstrated by the ChIP assay. Luciferase reporter assay indicated the possible transcriptional regulation of PAR-4 by high glucose. Beside PKC and NF-κB activation, high glucose mediated-ROS generation via NAD(P)H oxidase was also found to contribute as selective inhibitors to NAD(P)H oxidase prevented the high glucose regulation of PAR-4 in human vascular SMCs. Like high glucose, other pro-oxidants such as Ang-II or exogenous H2O2 could enhance PAR-4 expression, probably via PKC dependent ROS generation and NF-κB activation (Mohan et al. 2007; Rask-Madsen & King 2005). This selective PAR-4 upregulation by high glucose was associated with enhanced SMC migration, intracellular calcium signaling and inflammatory gene expression in responses to thrombin or PAR-4AP but not to PAR-1AP in human vascular SMCs. The positive immunoreactivity to PAR-4 and its colocalization with SMCs was seen in the vicinity of the intimal plaque region of diabetic atherosclerotic plaques. The present study provides the first evidence of a direct regulatory action of high glucose on expression and function of vascular thrombin receptors. Findings of the study highlight a unique role of PAR-4 in settings of hyperglycemia, which is likely to contribute to the enhanced cellular effects of thrombin and exaggerated cardiovascular complications of diabetes. This study suggests that targeting only PAR-1 may not be sufficient to treat diabetes associated atherothrombotic complications and sights that PAR-4 may be a novel and potential target for antithrombotic and antirestenotic therapeutics, specially in diabetic patients. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 15.07.2010 | |||||||
| Dateien geändert am: | 15.07.2010 | |||||||
| Promotionsantrag am: | 30.04.2010 | |||||||
| Datum der Promotion: | 16.06.2010 |
