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 [H-3]proline and [H-3]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 A(2) antagonist) and 1,3-dipropyl-8-(p-sulfophenyl)xanthine (A(1)/A(2) receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A(1) antagonist), thus excluding the participation of A(1) receptors. The lack of effect of CGS21680 (selective A(2A) agonist) excluded involvement of A(2A) receptors, thus suggesting a major role for A(2B) receptors. Comparisons of the inhibitory potencies of N-6-cyclopentyladenosine (selective A(1) agonist), 5'-N-ethylcarboxamidoadenosine (A(1)/A(2) agonist), and 5'-N-methylcarboxamidoadenosine (A(1)/A(2) agonist) were consistent with that of an A(2B) receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A(2B) receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.