Deletion of the ?2-adrenergic receptor prevents the development of cardiomyopathy in mice.

ABSTRACT: Beta adrenergic receptor (?-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that ?1-AR signaling is cardiotoxic whereas ?2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether ?2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of ?1 vs ?2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with ?1-/- or ?2-/- mice. Deletion of the ?2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the ?1-AR reduced survival. Pathologic changes in Ca(2+) handling were reversed in the absence of ?2-ARs: peak Ca(2+) and SR Ca(2+) were decreased in MLP-/- and ?1+/-/MLP-/- but restored in ?2-/-MLP-/-. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca(2+), recapitulating changes observed in the ?2-/-/MLP-/-. The L-type Ca(2+) blocker verapamil significantly decreased cardiac function in ?2-/-MLP-/- vs WT. We next tested if the protective effects of ?2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, ?2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca(2+) and Ca(2+) release. Deletion of ?2-ARs prevents the development of MLP-/- cardiomyopathy via positive modulation of Ca(2+) due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where ?2-ARs were found to be cardioprotective, in these two models, ?2-AR signaling appears to be deleterious, potentially through negative regulation of Ca(2+) dynamics.

SUBMITTER: Fajardo G 

PROVIDER: S-EPMC3791213 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature