Abstract
We have shown that adenosine administration is capable of reversing fibrosis in the carbon tetrachloride-induced rat cirrhotic liver, stimulating the diminished proliferative potential of the cirrhotic liver. To characterize adenosine actions on liver cellular proliferation, we used rats subjected to one-third partial hepatectomy (PH). In PH animals acutely administered with adenosine (25–200 mg/kg b.w.), parameters indicative of cell proliferation were determined. In addition, hepatocyte growth factor (HGF), epidermal growth factor, and transforming growth factor-α, cyclins, members of the E2F family, proto-oncogenes, and adenosine-receptors were determined through Western blot analyses. Adenosine (100 mg/kg body weight) induced an earlier increase in liver cell proliferation as evidenced by enhanced levels of proliferating cell nuclear antigen, nuclear Ki-67 antigen, and those for cyclins (D1, E, A, and B1), as well as by an increased mitotic index. These effects were also accompanied for a long-lasting increase of serum and liver levels of HGF and liver expression of c-Met and HGF liver activator. Adenosine effects on cell proliferation could be mediated by an early increase in E2F-1 and by that of c-Myc, despite the fact that phosphorylation of the Rb protein and expression of E2F-3 were decreased. Moreover, the liver amount of specific receptors for adenosine was not significantly changed by PH and/or adenosine treatment. In conclusion, these data suggest that adenosine actions can accelerate and increase proliferation in a “primed” liver, mainly through enhancing c-Myc, E2F family, cell-cycle cyclins, and HGF expression. Therefore, these pharmacological adenosine effects suggest a modulating role for the nucleoside on mitogenic events once the liver has been triggered to proliferate.
- PH, partial hepatectomy
- HGF, hepatocyte growth factor
- HGFLA, HGF liver activator
- PCNA, proliferating cell nuclear antigen
- TGF-α, transforming growth factor
- TK, thymidine kinase
- WB, Western blot
- PBS, phosphate-buffered saline
- ADU, arbitrary densitometry units.
Footnotes
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E.M.-C. was supported by a fellowship from the Consejo Nacional de Ciencia y Tecnología (CONACyT) for Ph.D. studies.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- Received May 27, 2009.
- Accepted July 27, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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