Differential cardioprotective/cardiotoxic effects mediated by ß-adrenergic receptor subtypes

Recent data suggest that beta-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of beta 1- vs. beta 2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to beta 1, beta 2, and beta 1/beta 2 knockout ((-/-)) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and beta 1(-/-) mice showed no acute cardiovascular effects, whereas beta 2(-/-) mice all died within 30 min. The additional deletion of the beta 1- receptor ( beta 1/ beta 2(-/-)) totally rescued this toxicity. beta 2(-/-) mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued beta 2(-/-) mice from this acute toxicity. The enhanced toxicity in beta 2(-/-) mice was also recapitulated in wild-type mice with the beta 2-selective antagonist ICI-118,551, although the rescue effect of the beta 1-deletion was not recapitulated using the beta 1-selective antagonist metoprolol or the nonselective beta-antagonist propranolol. These data suggest that beta 2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas beta 1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate beta-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these beta-adrenergic receptor subtypes in vivo.