Rac inhibition reverses the phenotype of fibrotic fibroblasts.
BACKGROUND:Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce alpha-smooth muscle actin (alpha-SMA)...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-10-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2757676?pdf=render |
| _version_ | 1819077833490694144 |
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| author | Shi-wen Xu Shangxi Liu Mark Eastwood Sonali Sonnylal Christopher P Denton David J Abraham Andrew Leask |
| author_facet | Shi-wen Xu Shangxi Liu Mark Eastwood Sonali Sonnylal Christopher P Denton David J Abraham Andrew Leask |
| author_sort | Shi-wen Xu |
| collection | DOAJ |
| description | BACKGROUND:Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce alpha-smooth muscle actin (alpha-SMA), type I collagen and CCN2 (connective tissue growth factor, CTGF). The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies. METHODS AND FINDINGS:Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was also blocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. Rac1 activity was blocked by PI3kinase/Akt inhibition. Basal fibroblast activity was not affected by NSC23766. CONCLUSION:Rac inhibition may be considered as a novel treatment for the fibrosis observed in SSc. |
| first_indexed | 2024-12-21T19:03:29Z |
| format | Article |
| id | doaj.art-0f55c637255d49a68197bec723715d75 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T19:03:29Z |
| publishDate | 2009-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0f55c637255d49a68197bec723715d752022-12-21T18:53:24ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-10-01410e743810.1371/journal.pone.0007438Rac inhibition reverses the phenotype of fibrotic fibroblasts.Shi-wen XuShangxi LiuMark EastwoodSonali SonnylalChristopher P DentonDavid J AbrahamAndrew LeaskBACKGROUND:Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce alpha-smooth muscle actin (alpha-SMA), type I collagen and CCN2 (connective tissue growth factor, CTGF). The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies. METHODS AND FINDINGS:Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was also blocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. Rac1 activity was blocked by PI3kinase/Akt inhibition. Basal fibroblast activity was not affected by NSC23766. CONCLUSION:Rac inhibition may be considered as a novel treatment for the fibrosis observed in SSc.http://europepmc.org/articles/PMC2757676?pdf=render |
| spellingShingle | Shi-wen Xu Shangxi Liu Mark Eastwood Sonali Sonnylal Christopher P Denton David J Abraham Andrew Leask Rac inhibition reverses the phenotype of fibrotic fibroblasts. PLoS ONE |
| title | Rac inhibition reverses the phenotype of fibrotic fibroblasts. |
| title_full | Rac inhibition reverses the phenotype of fibrotic fibroblasts. |
| title_fullStr | Rac inhibition reverses the phenotype of fibrotic fibroblasts. |
| title_full_unstemmed | Rac inhibition reverses the phenotype of fibrotic fibroblasts. |
| title_short | Rac inhibition reverses the phenotype of fibrotic fibroblasts. |
| title_sort | rac inhibition reverses the phenotype of fibrotic fibroblasts |
| url | http://europepmc.org/articles/PMC2757676?pdf=render |
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