AUTHOR=Ahsan Md. Kaimul , Mehal Wajahat Z. 

TITLE=Activation of adenosine receptor A2A increases HSC proliferation and inhibits death and senescence by down-regulation of p53 and Rb

JOURNAL=Frontiers in Pharmacology

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2014.00069

DOI=10.3389/fphar.2014.00069

ISSN=1663-9812

ABSTRACT=<p><bold>Background and Aims:</bold> During fibrosis hepatic stellate cells (HSC) undergo activation, proliferation, and senescence but the regulation of these important processes is poorly understood. The adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>) is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A<sub>2A</sub> has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism.</p><p><bold>Methods</bold>: The ability of adenosine to regulate p53 and Rb protein levels, proliferation, apoptosis and senescence was tested in the human HSC cell line LX-2 and rat primary HSC.</p><p><bold>Results</bold>: Adenosine receptor activation down-regulates p53 and Rb protein levels, increases BrdU incorporation and increases cell survival in LX-2 cells and in primary rat HSC. These effects of NECA were reproduced by an adenosine A<sub>2A</sub> receptor specific agonist (CGS21680) and blocked by a specific antagonist (ZM241385). By day twenty-one of culture primary rat HSC entered senescence and expressed β-gal which was significantly inhibited by NECA. Furthermore, NECA induced down regulation of p53 and Rb and Rac1, and decreased phosphorylation of p44-42 MAP Kinase in LX-2 cells and primary rat HSC. These effects were reproduced by the cAMP analog 8-Bromo-cAMP, and the adenylyl cyclase activator forskolin, and were blocked by PKA inhibitors.</p><p><bold>Conclusions</bold>: These results demonstrate that A<sub>2A</sub> receptor regulates a number of HSC fate decisions and induces greater HSC proliferation, reduces apoptosis and senescence by decreasing p53 and Rb through cAMP-PKA/Rac1/p38 MAPK pathway. This provides a mechanism for adenosine induced HSC regulation and liver fibrosis.</p>