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

D Bernstein, G Fajardo, M Zhao… - American Journal …, 2005 - journals.physiology.org
D Bernstein, G Fajardo, M Zhao, T Urashima, J Powers, G Berry, BK Kobilka
American Journal of Physiology-Heart and Circulatory Physiology, 2005journals.physiology.org
Recent data suggest that β-adrenergic receptor subtypes couple differentially to signaling
pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of β1-vs.
β2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to β1,
β2, and β1/β2 knockout (−/−) and wild-type mice. Expression and activation of MAPKs were
measured. Wild-type and β1−/− mice showed no acute cardiovascular effects, whereas
β2−/− mice all died within 30 min. The additional deletion of the β1-receptor (β1/β2−/−) …
Recent data suggest that β-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of β1- vs. β2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to β1, β2, and β1/β2 knockout (−/−) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and β1−/− mice showed no acute cardiovascular effects, whereas β2−/− mice all died within 30 min. The additional deletion of the β1-receptor (β1/β2−/−) totally rescued this toxicity. β2−/− 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 β2−/− mice from this acute toxicity. The enhanced toxicity in β2−/− mice was also recapitulated in wild-type mice with the β2-selective antagonist ICI-118,551, although the rescue effect of the β1-deletion was not recapitulated using the β1-selective antagonist metoprolol or the nonselective β-antagonist propranolol. These data suggest that β2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas β1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate β-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these β-adrenergic receptor subtypes in vivo.
American Physiological Society