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Background and Aims:  During fibrosis hepatic stellate cells (HSC) undergo activation, proliferation, and senescence but the regulation of these important processes is poorly understood. The adenosine A 2A  receptor (A 2A ) is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A 2A  has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism.   Methods : 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.   Results : 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 2A  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.   Conclusions : These results demonstrate that A 2A  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.

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