The plant alkaloid conophylline inhibits matrix formation of fibroblasts
| Autor: | Sonoko Hatano, Yoshitaka Hosokawa, Hideto Watanabe, Akinobu Ota, Kazuo Umezawa, Kazuhisa Yokoo, Davide Vigetti, Takehiko Tezuka, Sivasundaram Karnan, Alberto Passi, Katsuhiko Matsuura |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
anti-fibrotic collagen conophylline extracellular matrix fibroblast fibrosis hyaluronan stellate cell transforming growth factor beta (TGF-B) vinca alkaloid MAP Kinase Signaling System Glycobiology and Extracellular Matrices Smad2 Protein Biochemistry Gene Expression Regulation Enzymologic Extracellular matrix Mothers against decapentaplegic homolog 2 03 medical and health sciences Versicans 0302 clinical medicine Extracellular medicine Humans Smad3 Protein Phosphorylation Fibroblast Vinca Alkaloids Molecular Biology Cells Cultured Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 biology Chemistry Kinase Cell Biology Fibroblasts Extracellular Matrix Cell biology 030104 developmental biology medicine.anatomical_structure Protein Biosynthesis 030220 oncology & carcinogenesis Hepatic stellate cell biology.protein Versican Collagen Hyaluronan Synthases Transforming growth factor |
| Zdroj: | Journal of Biological Chemistry. 293:20214-20226 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.005783 |
| Popis: | Conophylline is a Vinca alkaloid from leaves of the tropical plant Ervatamia microphylla and has been shown to mimic the effect of the growth and differentiation factor activin A on pancreatic progenitor cells. However, activin A stimulates fibrosis of pancreatic stellate cells, whereas conophylline inhibits it, suggesting that this compound may serve as an antifibrotic drug. Here we investigated the effects of conophylline on human foreskin fibroblasts, especially focusing on extracellular matrix (ECM) proteins. A gene microarray analysis revealed that conophylline remarkably suppressed expression of the gene for hyaluronan synthase 2 (HAS2) and of its antisense RNA, whereas the expression of collagen genes was unaffected. Of note, immunostaining experiments revealed that conophylline substantially inhibits incorporation of versican and collagens into the ECM in cells treated with transforming growth factor β (TGFβ), which promotes collagen synthesis, but not in cells not treated with TGFβ. Moreover, a protein biosynthesis assay disclosed that conophylline decreases collagen biosynthesis, concomitant with a decrease in total protein biosynthesis, indicating that conophylline-mediated inhibition of fibrosis is not specific to collagen synthesis. Conophylline affected neither TGFβ-induced nuclear translocation of SMAD family member 2/3 (SMAD2/3) nor phosphorylation of SMAD2. However, conophylline substantially inhibited phosphorylation of extracellular signal–regulated kinase 1/2 (ERK1/2), suggesting that conophylline inhibits HAS2 expression via TGFβ-mediated activation of the ERK1/2 pathway. Taken together, our results indicate that conophylline may be a useful inhibitor of ECM formation in fibrosis. |
| Databáze: | OpenAIRE |
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