| First Author | Bernstein D | Year | 2005 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 289 |
| Issue | 6 | Pages | H2441-9 |
| PubMed ID | 16040722 | Mgi Jnum | J:104748 |
| Mgi Id | MGI:3612742 | Doi | 10.1152/ajpheart.00005.2005 |
| Citation | Bernstein D, et al. (2005) Differential cardioprotective/cardiotoxic effects mediated by beta-adrenergic receptor subtypes. Am J Physiol Heart Circ Physiol 289(6):H2441-9 |
| abstractText | Recent data suggest that beta-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of beta1- vs. beta2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to beta1, beta2, and beta1/beta2 knockout (-/-) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and beta1-/- mice showed no acute cardiovascular effects, whereas beta2-/- mice all died within 30 min. The additional deletion of the beta1-receptor (beta1/beta2-/-) totally rescued this toxicity. beta2-/- 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 beta2-/- mice from this acute toxicity. The enhanced toxicity in beta2-/- mice was also recapitulated in wild-type mice with the beta2-selective antagonist ICI-118,551, although the rescue effect of the beta1-deletion was not recapitulated using the beta1-selective antagonist metoprolol or the nonselective beta-antagonist propranolol. These data suggest that beta2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas beta1-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. |
