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Differential cardioprotective/cardiotoxic effects mediated by -adrenergic receptor subtypes

Departments of ¹Pediatrics, ²Pathology, and ³Molecular and Cellular Physiology, Stanford University, Stanford, California

Submitted 5 January 2005 ; accepted in final form 13 July 2005

Recent data suggest that -adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of 1- vs. 2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to 1, 2, and 1/2 knockout (^–/–) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and 1^–/– mice showed no acute cardiovascular effects, whereas 2^–/– mice all died within 30 min. The additional deletion of the 1-receptor (1/2^–/–) totally rescued this toxicity. 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 2^–/– mice from this acute toxicity. The enhanced toxicity in 2^–/– 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 1-adrenergic 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.

cardiomyopathy; anthracycline; adrenergic receptor; cell signaling; -blocker; mitogen-activated protein kinase

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