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This Article Full Text Full Text (PDF) All Versions of this Article: 287/6/H2478    most recent 00217.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Villarreal, F. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Villarreal, F.

Functional effects of enhancing or silencing adenosine A_2b receptors in cardiac fibroblasts

¹Department of Medicine, University of California, San Diego 92103-8412; and ²Metabasis Therapeutics Incorporated, San Diego, California 92121

Submitted 10 March 2004 ; accepted in final form 26 July 2004

Cardiac fibroblasts (CF) express adenosine (ADO) receptors, and pharmacological evidence suggests the possible involvement of the A₂ (A_2a and A_2b) receptor (A_2aR and A_2bR) subtypes in inhibiting cell functions involved in fibrosis. The main objective of this study was to define the contributions of A_2a and/or A_2b receptors in modulating ADO-induced decreases in CF functions. For this purpose, CF were either treated pharmacologically or had the A_2aR or A_2bR levels modified through the use of recombinant adenovirus or siRNA. The assessment of mRNA expression in adult rat CF yielded evidence for A₁R, A_2bR, A_2aR, and A₃R. Endogenously or exogenously enhanced ADO significantly inhibits CF proliferation, collagen, and protein synthesis. A₂R and A_2aR agonists, although capable of inhibiting CF protein and collagen synthesis, were unable to define the contributions derived from A_2aR or A_2bR. Overexpression of A_2bR in CF yielded significant decreases in basal levels of collagen and protein synthesis and correlated with increases in cAMP levels. However, at higher doses of ADO receptor agonists, significant increases in protein and collagen synthesis were observed. CF with underexpression of A_2bR yielded increases in protein and collagen synthesis. In contrast, A_2aR underexpression did not modify ADO-induced decreases in CF protein or collagen synthesis. In conclusion, results derived from the molecular manipulation of receptor levels indicate that A_2bR are critically involved in ADO-mediated inhibition of CF functions.

collagen deposition; extracellular matrix; remodeling

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