Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes
American Journal of Physiology. Heart and Circulatory Physiology
Differential cardioprotective/cardiotoxic effects mediated by ␤-adrenergic receptor subtypes. Recent data suggest that ␤-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of ␤1vs. ␤2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to ␤1, ␤2, and ␤1/␤2 knockout ( Ϫ/Ϫ ) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and ␤1 Ϫ/Ϫ mice showed
... acute cardiovascular effects, whereas ␤2 Ϫ/Ϫ mice all died within 30 min. The additional deletion of the ␤1-receptor (␤1/ ␤2 Ϫ/Ϫ ) totally rescued this toxicity. ␤2 Ϫ/Ϫ 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 ␤2 Ϫ/Ϫ mice from this acute toxicity. The enhanced toxicity in ␤2 Ϫ/Ϫ mice was also recapitulated in wild-type mice with the ␤2-selective antagonist ICI-118,551, although the rescue effect of the ␤1-deletion was not recapitulated using the ␤1-selective antagonist metoprolol or the nonselective ␤-antagonist propranolol. These data suggest that ␤2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas ␤1adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate ␤-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these ␤-adrenergic receptor subtypes in vivo.