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Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition
Author(s) -
Sohail Muhammad A.,
Hashmi Ardeshir Z.,
Hakim Wyel,
Watanabe Azuma,
Zipprich Alexander,
Groszmann Roberto J.,
Dranoff Jonathan A.,
Torok Natalie J.,
Mehal Wajahat Z.
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22589
Subject(s) - stress fiber , microbiology and biotechnology , adenosine , actin , hepatic stellate cell , contraction (grammar) , rho associated protein kinase , chemistry , biology , focal adhesion , biophysics , signal transduction , biochemistry , endocrinology
The Rho/ROCK pathway is activated in differentiated hepatic stellate cells (HSCs) and is necessary for assembly of actin stress fibers, contractility, and chemotaxis. Despite the importance of this pathway in HSC biology, physiological inhibitors of the Rho/ROCK pathway in HSCs are not known. We demonstrate that adenosine induces loss of actin stress fibers in the LX‐2 cell line and primary HSCs in a manner indistinguishable from Rho/ROCK inhibition. Loss of actin stress fibers occurs via the A2a receptor at adenosine concentrations above 10 μM, which are present during tissue injury. We further demonstrate that loss of actin stress fibers is due to a cyclic adenosine monophosphate, protein kinase A–mediated pathway that results in Rho inhibition. Furthermore, a constitutively active Rho construct can inhibit the ability of adenosine to induce loss of actin stress fibers. Actin stress fibers are required for HSC contraction, and we demonstrate that adenosine inhibits endothelin‐1 and lysophosphatidic acid–mediated HSC contraction. We propose that adenosine is a physiological inhibitor of the Rho pathway in HSCs with functional consequences, including loss of HSC contraction. (H EPATOLOGY 2009;49:185‐194)