Abstract
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.
Highlights
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
We investigated the effects of CNP, a Vinca alkaloid that mimics activin A function, on fibroblast behavior and formation of the extracellular matrix (ECM)
The interesting features of this study were as follows: CNP dramatically inhibits HAS 1, hyaluronan synthase 2 (HAS2), and HAS2 AS expression, resulting in a decrease in HA secretion; CNP inhibits cell proliferation and biosynthesis of collagens at the same ratio with total protein biosynthesis; CNP inhibits versican incorporation into the ECM; CNP inhibits TGF-mediated differentiation of fibroblasts toward myofibroblasts; and CNP does not affect Smad2/3 signaling, it inhibits extracellular signal–regulated kinase 1/2 (ERK1/2) activation, which may be responsible for CNP action
Summary
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. Activin A stimulates fibrosis of pancreatic stellate cells, whereas conophylline inhibits it, suggesting that this compound may serve as an antifibrotic drug. Conophylline (CNP) is a Vinca alkaloid extracted from leaves of the tropical plant Ervatamia microphylla [4] This compound was initially found to mimic the effect of activin A on the differentiation of pancreatic progenitor cells [5]. Activin A up-regulates the expression of ␣-smooth muscle actin (␣SMA) and collagens of pancreatic stellate cells toward pancreatic fibrosis [7], CNP suppresses their expression [5].
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