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Salvianolic acid B lowers portal pressure in cirrhotic rats and attenuates contraction of rat hepatic stellate cells by inhibiting RhoA signaling pathway.
- Source :
-
Laboratory investigation; a journal of technical methods and pathology [Lab Invest] 2012 Dec; Vol. 92 (12), pp. 1738-48. Date of Electronic Publication: 2012 Sep 17. - Publication Year :
- 2012
-
Abstract
- The contraction of hepatic stellate cells (HSCs) has a critical role in the regulation of intrahepatic vascular resistance and portal hypertension. Previous studies have confirmed that salvianolic acid B (Sal B) is effective against liver fibrosis. In the present study, we evaluated the effect of Sal B on portal hypertension and on HSCs contractility. Liver cirrhosis was induced in rats by peritoneal injection of dimethylnitrosamine and the portal pressure was measured. HSCs contraction was evaluated by collagen gel contraction assay. Glycerol-urea gel electrophoresis was performed to determine the phosphorylation of myosin light chain 2 (MLC2). F-actin stress fiber polymerization was detected by fluorescein isothiocyanate-labeled phalloidin. Intracellular Ca(2+) and RhoA signaling activation were also measured. Sal B effectively reduced the portal pressure in DMN-induced cirrhotic rats. It decreased the contraction by endothelin-1 (ET-1)-activated HSCs by ∼66.5% and caused the disassembly of actin stress fibers and MLC2 dephosphorylation. Although Sal B reduced ET-1-induced intracellular Ca(2+) increase, blocking Ca(2+) increase completely by BAPTA-AM, a Ca(2+) chelator, barely affected the magnitude of contraction. Sal B decreased ET-1-induced RhoA and Rho-associated coiled coil-forming protein kinase (ROCK) II activation by 66.84% and by 76.79%, respectively, and inhibited Thr(696) phosphorylation of MYPT1 by 80.09%. In vivo, Sal B lowers the portal pressure in rats with DMN-induced cirrhosis. In vitro, Sal B attenuates ET-1-induced HSCs contraction by inhibiting the activation of RhoA and ROCK II and the downstream MYPT1 phosphorylation at Thr(696). We consider Sal B a potential candidate for the pharmacological treatment of portal hypertension.
- Subjects :
- Actins metabolism
Animals
Cardiac Myosins metabolism
Cells, Cultured
Dimethylnitrosamine toxicity
Endothelin-1 metabolism
Hepatic Stellate Cells metabolism
Histocytochemistry
Liver chemistry
Liver cytology
Liver metabolism
Liver pathology
Liver Cirrhosis, Experimental chemically induced
Liver Cirrhosis, Experimental metabolism
Liver Cirrhosis, Experimental pathology
Male
Myosin Light Chains metabolism
Phosphorylation drug effects
Protein Phosphatase 1 metabolism
Rats
Rats, Sprague-Dawley
Stress Fibers metabolism
rho-Associated Kinases metabolism
Benzofurans pharmacology
Hepatic Stellate Cells drug effects
Liver Cirrhosis, Experimental physiopathology
Portal Pressure drug effects
Signal Transduction drug effects
rhoA GTP-Binding Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0307
- Volume :
- 92
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Laboratory investigation; a journal of technical methods and pathology
- Publication Type :
- Academic Journal
- Accession number :
- 22986787
- Full Text :
- https://doi.org/10.1038/labinvest.2012.113