The Role of Endothelin-1 (ET-1) and Nuclear Factor Erythroid-2-related Factor 2 (Nrf-2) in Cyclosporine-A-induced Gingival Overgrowth
| Autor: | Chin, Yu-Tang, 金玉堂 |
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| Rok vydání: | 2011 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 99 The thesis article is combined two parts of studies. First part of study was aimed to evaluate the expression and bioactivities of endothelin-1 (ET-1) in gingiva during cyclosporine A (CsA) treatment. On the other hand, second part was to examine the role of Nrf-2 in the regulation of CsA-stimulated HO-1 expression in human gingival fibroblasts (HGFs). In the first part of study, we established edentulous ridges in rats and fed them with 30 mg/kg/day CsA or mineral oil for 4 weeks. The expression of ET-1, its receptors, proliferating cell nuclear antigen (PCNA) and inducible nitric oxide synthase (iNOS) were examined through a reverse transcription polymerase chain reaction (RT-PCR) and/or immunohistochemistry. The relationship of the endothelin receptors A and B (ETA and ETB) in CsA-enhanced expression of PCNA and iNOS were examined in cultured HGFs pretreated with receptor antagonists, by immunocytochemistry and RT-PCR, respectively. In the second part, Nrf-2 siRNA (siNrf-2), NF-κB, kinase inhibitors, and sulforaphane (SFN) were used to examine the nuclear translocation of Nrf-2 and expression of HO-1 and transforming growth factor-β1 (TGF-β1) in cells. The results of first part revealed that mRNA and protein expressions of ET-1, ETA and ETB, as well as of PCNA and iNOS, were significantly greater in CsA-treated edentulous gingiva if compared with control. In HGFs, 10 and 100 ng/ml CsA enhanced the mRNA expression of ET-1, ETA and ETB. Additionally, CsA-enhanced PCNA expression was reduced by blockade of ETA, whereas iNOS expression was reduced by blockade of ETB. In the results second part, treatment with siNrf-2 but not with an NF-B inhibitor reduced CsA-stimulated HO-1 mRNA expression. ERK inhibition significantly decreased CsA-stimulated Nrf-2 nuclear translocation and HO-1 mRNA expression. Pretreatment with SFN showed that HO-1 plays a role in attenuating CsA-mediated TGF-β1 expressions. Based on these two studies, we suggest that CsA upregulates the gingival expression of ET-1 and its receptors; and ETA and ETB have different bioactivities, ETA being involved in cell proliferation and ETB being associated with iNOS expression. Furthermore, CsA-stimulated HO-1 expression is mediated through the activation of ERK and that Nrf-2 plays a protective role against CsA-induced gingival fibrosis by modulating collagen turnover-related genes. These findings of the thesis article might partially elucidate the mechanism of CsA-induced gingival overgrowth. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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