ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1.
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.
Kawada
N
N
Department of Internal Medicine, Department of Anatomy, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno, Osaka, 545-8585, Japan.
Seki
S
S
Kuroki
T
T
Kaneda
K
K
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006975:Hypertension, Portal / Q000139:chemically induced / Q000188:drug therapy; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011169:Portal Vein / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases
D000199:Actins; D000577:Amides; D000959:Antihypertensive Agents; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases