A2B Adenosine Receptors Mediate the Anti-Mitogenic Effects of Adenosine in Cardiac Fibroblasts
Adenosine inhibits growth of CFs; however, the adenosine receptor subtype that mediates this anti-mitogenic effect remains undefined. Using specific ADE receptor antagonists and agonists and antisense oligonucleotides (OLIGO) against A2B receptors, we investigated the role of A2B receptors in inhibiting cardiac fibroblast growth. PDGF (25ng/ml)-induced DNA synthesis, cell number and collagen synthesis in CFs were inhibited by A2 (chloroadenosine [Cl-Ad]and MECA), but not by A1 (CPA), A2a (CGS21680) or A3 (AB-MECA),receptor agonists.The inhibitory effects of 1μM MECA and Cl-Ad were reversed by A1/A2 (DPSPX; 10nM), but not by A1 (DPCPX; 10nM), receptor antagonists. In CFs treated with antisense, but not sense or scrambled, OLIGOs to the A2B receptor, both basal and PDGF-induced DNA synthesis was enhanced by 70±4% and 64±5% respectively. Moreover, the inhibitory effects of Cl-Ad and MECA were completely abolished in CFs treated with antisense, but not sense and scrambled, OLIGOs. In conclusion, A2B receptors mediate the anti-mitogenic effects of adenosine suggesting that A2B receptors are importantly involved in the regulation of CF biology. Thus, A2B receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation.