A novel cardioprotective role of RhoA: new signaling mechanism for adenosine

Adenosine exerts a potent cardioprotective effect that is mediated by adenosine A(1) and A(3) receptors. The signaling pathways activated by the A(1) and A(3) receptors are distinct and involve selective coupling to phospholipases C and D, respectively. The objective of our study was to elucidate the signaling mechanism that mediates the coupling of each receptor to its respective phospholipase and to test the role of RhoA as a novel mediator leading from adenosine receptors to cardioprotection. C3 transferase and dominant negative RhoA (RhoAT19N) blocked the A(3) receptor-mediated phospholipase D activation and cardioprotection but had no effect on A(1) receptor-mediated phospholipase C activation or cardioprotection. In contrast, pertussis toxin treatment caused a greater inhibition of the diacylglycerol accumulation induced by the A(1) agonist than by the A(3) agonist, and it completely abrogated the A(1) agonist-mediated cardioprotection. Thus, adenosine A(1) and A(3) receptors are linked to different G-proteins. The A(3) receptor is coupled via RhoA to activate phospholipase D in exerting its cardioprotective effect, whereas the A(1) receptor is linked via G(i) to phospholipase C to produce cardioprotective responses. The present study identifies a novel role for RhoA and further suggests its importance in regulating cardiac cellular function.