Adenosine inhibits collagen and protein synthesis in cardiac fibroblasts: role of A2B receptors.
The objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast-derived) adenosine on [3H]proline and [3H]leucine incorporation, which are reliable markers of collagen and total protein synthesis, respectively, in rat left ventricular cardiac fibroblasts. Growth-arrested confluent cardiac fibroblast monolayers were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (adenosine deaminase inhibitor), (2) dipyridamole (adenosine transport blocker), and (3) iodotubericidin (adenosine kinase inhibitor). All agents inhibited in a concentration-dependent fashion FCS-induced [3H]proline and [3H]leucine incorporation. These effects were blocked by KF17837 (selective A2 antagonist) and 1,3-dipropyl-8-(p-sulfophenyl)xanthine (A1/A2 receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A1 antagonist), thus excluding the participation of A1 receptors. The lack of effect of CGS21680 (selective A2A agonist) excluded involvement of A2A receptors, thus suggesting a major role for A2B receptors. Comparisons of the inhibitory potencies of N6-cyclopentyladenosine (selective A1 agonist), 5'-N-ethylcarboxamidoadenosine (A1/A2 agonist), and 5'-N-methylcarboxamidoadenosine (A1/A2 agonist) were consistent with that of an A2B receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A2B receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.
Dubey
R K
RK
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, PA 15213-2582, USA. dubey@novell2.dept-med.pitt.edu
Gillespie
D G
DG
Jackson
E K
EK
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism
D002317:Cardiovascular Agents; D011506:Proteins; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D015762:2-Chloroadenosine; D003094:Collagen; D000241:Adenosine