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Title: Both Ca2+-dependent and -independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine
Authors: Laleman, Wim ×
Van Landeghem, Lien
Severi, Tamara
Vander Elst, Ingrid
Zeegers, Marcel
Bisschops, Raf
van Pelt, Jos
Roskams, Tania
Cassiman, David
Fevery, Johan
Nevens, Frederik #
Issue Date: Feb-2007
Publisher: Amer physiological soc
Series Title: American Journal of Physiology. Gastrointestinal and Liver Physiology vol:292 issue:2 pages:G556-G564
Abstract: Background: In chronic liver injury, hepatic stellate cells (HSC) have been implicated as regulators of sinusoidal vascular tone. We studied the relative role of Ca(2+)-dependent and Ca(2+)-independent contraction pathways in HSCs and correlated these findings to in-situ perfused cirrhotic rat livers. Methods: Contraction of primary rat HSCs was studied by a stress-relaxed-collagen-lattice model. Dose-response curves to the Ca(2+)-ionophore A23187 and to the calmodulin/myosin light-chain kinase-inhibitor W-7 served to study Ca(2+)-dependent pathways. Y-27632, staurosporin and calyculin, inhibitors of respectively Rho-kinase, protein-kinase C and myosin-light chain phosphatase, were used to investigate Ca(2+)-independent pathways. Actomyosin-interaction, the common end-target, was inhibited by butanedione monoxime [BDM]. The effect of W-7, Y-27632 and staurosporin on the intrahepatic vascular resistance (IHVR) was evaluated by in-situ perfusion of normal and thioacetamide (TAA) cirrhotic rat livers stimulated with methoxamine (n=25 each). Results: In vitro, HSC contraction was shown to be actomyosin-based with a regulating role for both Ca(2+)-dependent and -independent pathways. Although the former seem important, an important auxiliary role for the latter was illustrated through their involvement in the phenomenon of "Ca(2+)-sensitization". In vivo, preincubation of cirrhotic liver with Y-27632 10(-4)M and staurosporin 25nM, more than with W-7 10(-4)M, significantly reduced the hyperresponsiveness to methoxamine 10(-4)M by -66.8+/-1.3%, -52.4+/-2.7% and -28.7+/-2.8% respectively, whereas in normal liver this was significantly less: -43.1+/-4.2%, -40.2+/-4.2% and -3.8+/-6.3%. Conclusion: Taken together, these results suggest that HSC contraction is based on both Ca(2+)-dependent and -independent pathways, which were shown to be upregulated in the perfused cirrhotic liver, with a predominance of Ca(2+)-independent pathways. Key words: portal hypertension, intrahepatic vascular resistance, stress-relaxed matrix contraction, rhoA, protein kinase C.
ISSN: 0193-1857
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Research in GastroIntestinal Disorders
Translational Cell & Tissue Research
× corresponding author
# (joint) last author

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