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

Adenosine exerts a potent cardioprotective effect that is mediated by adeno sine 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 phospholi pases C and D, respectively. The objective of our study was to elucidate th e signaling mechanism that mediates the coupling of each receptor to its re spective phospholipase and to test the role of RhoA as a novel mediator lea ding from adenosine receptors to cardioprotection. C3 transferase and domin ant negative RhoA (RhoAT19N) blocked the A(3) receptor-mediated phospholipa se D activation and cardioprotection but had no effect on A(1) receptor-med iated phospholipase C activation or cardioprotection. In contrast, pertussi s toxin treatment caused a greater inhibition of the diacylglycerol accumul ation induced by the A(1) agonist than by the A(3) agonist, and it complete ly 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 cardioprot ective effect, whereas the A(1) receptor is linked via G(i) to phospholipas e C to produce cardioprotective responses. The present study identifies a n ovel role for RhoA and further suggests its importance in regulating cardia c cellular function.