ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1

Biochem Biophys Res Commun. 1999 Dec 20;266(2):296-300. doi: 10.1006/bbrc.1999.1823.

Abstract

By using a selective ROCK inhibitor Y-27632, the role of Rho-ROCK signaling in the function of hepatic stellate cells in culture was studied. Stellate cells maintained the "star-like" configuration of the quiescent stage in the presence of Y-27632, while the expression of smooth muscle alpha-actin and PDGF receptor beta was not affected by the agent. Serum-stimulated migration of the cells was significantly suppressed by Y-27632. The contraction of stellate cells induced by 5 nM endothelin-1 was attenuated by the agent in a dose-dependent manner. Formation of F-actin stress fibers and phosphorylation of myosin light chain was apparently reduced by Y-27632 even under the stimulation with endothelin-1. On the other hand, ex vivo liver perfusion experiment revealed that endothelin-1 (2 nM)-induced increase of portal vein constriction was almost completely inhibited by 20 microM Y-27632 with a concomitant improvement of hepatocyte degeneration. These results suggest that ROCK is one of the key regulators of stellate cell motility and that the clinical application of ROCK inhibitors such as Y-27632 should be considered in the reduction of portal hypertension in liver fibrosis and cirrhosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amides / pharmacology*
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Cell Movement / drug effects
  • Cell Size / drug effects
  • Cells, Cultured
  • Endothelin-1
  • Enzyme Inhibitors / pharmacology
  • Hypertension, Portal / chemically induced
  • Hypertension, Portal / drug therapy
  • Intracellular Signaling Peptides and Proteins
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Myosin Light Chains / metabolism
  • Phosphorylation
  • Portal Vein / drug effects*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Wistar
  • rho-Associated Kinases

Substances

  • Actins
  • Amides
  • Antihypertensive Agents
  • Endothelin-1
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Myosin Light Chains
  • Pyridines
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases