Adenosine Induces Loss of Actin Stress Fibers and Inhibits Contraction in Hepatic Stellate Cells via Rho Inhibition

被引:60
作者
Sohail, Muhammad A. [1 ]
Hashmi, Ardeshir Z. [1 ]
Hakim, Wyel [1 ]
Watanabe, Azuma [1 ]
Zipprich, Alexander [1 ]
Groszmann, Roberto J. [1 ]
Dranoff, Jonathan A. [1 ]
Torok, Natalie J. [3 ]
Mehal, Wajahat Z. [1 ,2 ]
机构
[1] Yale Univ, Sect Digest Dis, New Haven, CT 06520 USA
[2] Yale Univ, Dept Immunobiol, New Haven, CT 06520 USA
[3] Univ Calif Davis, Med Ctr, Div Gastroenterol & Hepatol, Davis, CA 95616 USA
关键词
GTP-BINDING PROTEIN; ROCK INHIBITOR; KINASE-A; ACTIVATION; GROWTH; PHOSPHORYLATION; ASSOCIATION; MORPHOLOGY; PERICYTES; DYNAMICS;
D O I
10.1002/hep.22589
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 mu M, 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. (HEPATOLOGY 2009;49:185-194.)
引用
收藏
页码:185 / 194
页数:10
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