| Autor: |
Ogawara, K, Kuldo, JM, Oosterhuis, K, Kroesen, BJ, Rots, MG, Trautwein, C, Kimura, T, Haisma, HJ, Molema, G |
| Přispěvatelé: |
Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Kidney Center (GKC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE) |
| Jazyk: |
angličtina |
| Rok vydání: |
2006 |
| Předmět: |
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| Zdroj: |
Arthritis Research and Therapy, 8(1):32. BioMed Central Ltd. |
| ISSN: |
1478-6354 |
| Popis: |
In order to selectively block nuclear factor kappa B (NF-kappa B)-dependent signal transduction in angiogenic endothelial cells, we constructed an alpha v beta 3 integrin specific adenovirus encoding dominant negative I kappa B (dnI kappa B) as a therapeutic gene. By virtue of RGD modification of the PEGylated virus, the specificity of the cell entry pathway of adenovirus shifted from coxsackiadenovirus receptor dependent to alpha v beta 3 integrin dependent entry. The therapeutic outcome of delivery of the transgene into endothelial cells was determined by analysis of cellular responsiveness to tumor necrosis factor (TNF)-alpha. Using real time reverse transcription PCR, mRNA levels of the cell adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, the cytokines/growth factors IL-6, IL-8 and vascular endothelial growth factor (VEGF)-A, and the receptor tyrosine kinase Tie-2 were assessed. Furthermore, levels of ICAM-1 protein were determined by flow cytometric analysis. RGD-targeted adenovirus delivered the dnl kappa B via alpha v beta 3 to become functionally expressed, leading to complete abolishment of TNF-alpha-induced up-regulation of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, VEGFA and Tie-2. The approach of targeted delivery of dnl kappa B into endothelial cells presented here can be employed for diseases such as rheumatoid arthritis and inflammatory bowel disease where activation of NF-kappa B activity should be locally restored to basal levels in the endothelium. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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