Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition.
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 muM, 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.
Sohail
Muhammad A
MA
Section of Digestive Diseases, Yale University, New Haven, CT 06520-8019, USA.
Hashmi
Ardeshir Z
AZ
Hakim
Wyel
W
Watanabe
Azuma
A
Zipprich
Alexander
A
Groszmann
Roberto J
RJ
Dranoff
Jonathan A
JA
Torok
Natalie J
NJ
Mehal
Wajahat Z
WZ
D000241:Adenosine / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D022502:Stress Fibers / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D019332:Endothelin-1; D008246:Lysophospholipids; D043705:Receptor, Adenosine A2A; D019830:Adenosine-5'-(N-ethylcarboxamide); D000242:Cyclic AMP; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine; C032881:lysophosphatidic acid