Source:http://linkedlifedata.com/resource/pubmed/id/17217948
Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
|
| pubmed:dateCreated |
2007-2-12
|
| pubmed:abstractText |
Proliferative vitreoretinopathy (PVR) is a major cause of the failure of rhegmatogenous retinal detachment surgery. The pathogenesis of PVR includes a fibrotic reaction of retinal pigment epithelial (RPE) cells caused by transforming growth factor (TGF)-beta. The cellular mechanisms by which TGF-beta induces extracellular matrix protein synthesis are not fully understood. In this study, we examined whether the RhoA/Rho-kinase pathway was involved in TGF-beta2-induced collagen expression in a human RPE cell line, ARPE-19. The roles of RhoA and Rho-kinase were evaluated using biochemical inhibitors, RhoA inhibitor, simvastatin and Rho-kinase inhibitor, Y27632. The effects of simvastatin or Y27632 on the type I collagen mRNA (COL1A1 and COL1A2) expression induced by TGF-beta2 were evaluated by real-time RT-PCR. The effects of simvastatin or Y27632 on type I collagen synthesis induced by TGF-beta2 were assessed by immunocytochemical analysis with anti-type I collagen antibody. To examine the effects of simvastatin or Y27632 on COL1A2 promoter activity induced by TGF-beta2, luciferase reporter assays were also performed. Moreover, the role of RhoA itself on COL1A2 promoter activity was assessed using the constructs of constitutively active RhoA and dominant-negative RhoA. RhoA was activated within 5 min after stimulation with TGF-beta2, and its activation persisted for as long as 1 h in a dose-dependent fashion. Preincubation of ARPE-19 with simvastatin (5 microM) or Y27632 (10 microM) significantly prevented TGF-beta2-induced COL1A1 and COL1A2 gene expression. Inhibition of RhoA/Rho-kinase markedly suppressed TGF-beta2-induced type I collagen synthesis in ARPE-19. Moreover, the blockage of RhoA/Rho-kinase inhibited the increase in COL1A2 promoter activity when induced by TGF-beta2. Constitutively active RhoA increased COL1A2 promoter activity in the presence or absence of TGF-beta2. Simvastatin and Y27632 reduced active RhoA-induced COL1A2 promoter activity. The dominant-negative RhoA inhibited COL1A2 promoter activity augmentation induced by TGF-beta2. In the luciferase assay using a mutation construct of the Smad binding site in COL1A2 promoter (Smad-mut/Luc), the treatment with simvastatin and Y27632 significantly reduced TGF-beta2 induction of Smad-mut/Luc promoter activity. On the other hand, both simvastatin and Y27632 significantly reduced CAGA12-Luc activity induced by TGF-beta2. These results indicate that the RhoA/Rho-kinase pathway plays a role in relaying TGF-beta2 signal transduction to type I collagen synthesis in RPE cells in a Smad-dependent and Smad-independent fashion. The RhoA/Rho-kinase pathway may be a therapeutic target for treating PVR.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/4-(5-benzo(1,3)dioxol-5-yl-4-pyridin...,
http://linkedlifedata.com/resource/pubmed/chemical/Amides,
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/Collagen Type I,
http://linkedlifedata.com/resource/pubmed/chemical/Dioxoles,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxymethylglutaryl-CoA...,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Simvastatin,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta2,
http://linkedlifedata.com/resource/pubmed/chemical/Y 27632,
http://linkedlifedata.com/resource/pubmed/chemical/rho-Associated Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/rhoA GTP-Binding Protein
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Mar
|
| pubmed:issn |
0014-4835
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
84
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
464-72
|
| pubmed:dateRevised |
2007-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:17217948-Amides,
pubmed-meshheading:17217948-Benzamides,
pubmed-meshheading:17217948-Cell Line,
pubmed-meshheading:17217948-Collagen Type I,
pubmed-meshheading:17217948-Depression, Chemical,
pubmed-meshheading:17217948-Dioxoles,
pubmed-meshheading:17217948-Enzyme Inhibitors,
pubmed-meshheading:17217948-Epithelial Cells,
pubmed-meshheading:17217948-Humans,
pubmed-meshheading:17217948-Hydroxymethylglutaryl-CoA Reductase Inhibitors,
pubmed-meshheading:17217948-Immunohistochemistry,
pubmed-meshheading:17217948-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:17217948-Pigment Epithelium of Eye,
pubmed-meshheading:17217948-Protein-Serine-Threonine Kinases,
pubmed-meshheading:17217948-Pyridines,
pubmed-meshheading:17217948-Signal Transduction,
pubmed-meshheading:17217948-Simvastatin,
pubmed-meshheading:17217948-Transfection,
pubmed-meshheading:17217948-Transforming Growth Factor beta2,
pubmed-meshheading:17217948-rho-Associated Kinases,
pubmed-meshheading:17217948-rhoA GTP-Binding Protein
|
| pubmed:year |
2007
|
| pubmed:articleTitle |
Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-beta2 in human retinal pigment epithelial cells.
|
| pubmed:affiliation |
Department of Ophthalmology, Oita University, Hasama-machi, Yufu-shi Oita 879-5593, Japan. itoyuji@med.oita-u.ac.jp
|
| pubmed:publicationType |
Journal Article
|