AI Article Synopsis

  • The Rho-kinase ROCK II is crucial for activating hepatic stellate cells (HSC), which contribute to chronic liver disease by promoting fibrosis and contraction.* -
  • Two ROCK inhibitors, Y-33075 and Y-27632, were tested on mouse and human HSCs, showing a significant reduction in cell contraction, fibrogenesis, and proliferation, with Y-33075 being ten times more effective than Y-27632.* -
  • Both inhibitors surprisingly increased HSC migration, suggesting that while they reduce harmful contraction in liver diseases, further evaluation is necessary to understand the implications of increased cell movement.*

Article Abstract

Background: The Rho-kinase ROCK II plays a major role in the activation of hepatic stellate cells (HSC), which are the key profibrotic and contractile cells contributing to the development of chronic liver disease. Inhibition of ROCK II ultimately blocks the phosphorylation of the myosin light chain (MLC) and thus inhibits stress fibre assembly and cell contraction. We investigated the effects of the ROCK inhibitors Y-33075 as well as Y-27632 in murine and human hepatic stellate cells.

Methods: Primary isolated HSC from FVB/NJ mice and the immortalized human HSC line TWNT-4 were culture-activated and incubated with Y-27632 and Y-33075 (10nM to 10μM) for 24h. Protein expression levels were analyzed by Western Blots and transcriptional levels of pro-fibrotic markers and proliferative markers were evaluated using real-time qPCR. Migration was investigated by wound-healing assay. Proliferation was assessed by BrdU assay. Contraction of HSC was measured using 3D collagen matrices after incubation with Y-27632 or Y-33075 in different doses.

Results: Both Rho-kinase inhibitors, Y-27632 and Y-33075, reduced contraction, fibrogenesis and proliferation in activated primary mouse HSC (FVB/NJ) and human HSC line (TWNT-4) significantly. Y-33075 demonstrated a 10-times increased potency compared to Y-27632. Surprisingly, both inhibitors mediated a substantial and unexpected increase in migration of HSC in FVB/NJ.

Conclusion: ROCK inhibition by the tested compounds decreased contraction but increased migration. Y-33075 proved more potent than Y27632 in the inhibition of contraction of HSCs and should be further evaluated in chronic liver disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888688PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270288PLOS

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  • Two ROCK inhibitors, Y-33075 and Y-27632, were tested on mouse and human HSCs, showing a significant reduction in cell contraction, fibrogenesis, and proliferation, with Y-33075 being ten times more effective than Y-27632.* -
  • Both inhibitors surprisingly increased HSC migration, suggesting that while they reduce harmful contraction in liver diseases, further evaluation is necessary to understand the implications of increased cell movement.*
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